Substituted Carboxylic Acids

ABSTRACT

The present invention relates to compounds and pharmaceutically acceptable salts of formula (I): 
     
       
         
         
             
             
         
       
     
     which are useful in the treatment of metabolic disorders related to insulin resistance or hyperglycemia. These compounds include inhibitors of protein tyrosine phosphatase (PTP-1B) that are useful in the treatment of diabetes and other PTP-1B mediated diseases, such as cancer, neurodegenerative diseases and the like. The compounds of the invention are also useful in pharmaceutical compositions and methods of treating the aforementioned conditions.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to substituted carboxylic acids and morespecifically to such compounds that are useful in the treatment ofdiabetes. More specifically, it relates to such compounds that arecapable of inhibiting Protein tyrosine phosphatase-1B (PTP-1B), which isa negative regulator of the insulin signaling pathway, and improvesinsulin-sensitivity.

2. Description of the Related Art

Protein tyrosine phosphatases are a large family of transmembrane orintracellular enzymes that dephosphorylate substrates involved in avariety of regulatory processes (Fischer et al., 1991, Science253:401-406). Protein tyrosine phosphatase-1B (PTP-1B) is anapproximately 50 kd intracellular protein, which is present in abundantamounts in various human tissues (Charbonneau et al., 1989, Proc. Natl.Acad. Sci. USA 86:5252-5256; Goldstein, 1993, Receptor 3:1-15).

Determining which proteins are substrates of PTP-1B has been ofconsiderable interest. One substrate which has aroused especial interestis the insulin receptor. The binding of insulin to its receptor resultsin autophosphorylation of the domain. This causes activation of theinsulin receptor tyrosine kinase, which phosphorylates the variousinsulin receptor substrate (IRS) proteins that propagate the insulinsignaling event further downstream to mediate insulin's variousbiological effects.

Seely et al., 1996, Diabetes 45:1379-1385 (“Seely”) studied therelationship of PTP-1B and the insulin receptor in vitro. Seelyconstructed a glutathione S-transferase (GST) fusion protein of PTP-1Bthat had a point mutation in the PTP-1B catalytic domain. Althoughcatalytically inactive, this fusion protein was able to bind to theinsulin receptor, as demonstrated by its ability to precipitate theinsulin receptor from purified receptor preparations and from whole celllysates derived from cells expressing the insulin receptor.

Ahmad et al., 1995, J. Biol. Chem. 270:20503-20508 used osmotic loadingto introduce PTP-1B neutralizing antibodies into rat KRC-7 hepatomacells. The presence of the antibody in the cells resulted in an increaseof 42% and 38%, respectively, in insulin stimulated DNA synthesis andphosphatidyinositol 3′ kinase activity. Insulin receptorautophosphorylation and insulin receptor substrate-1 tyrosinephosphorylation were increased 2.2 and 2.0-fold, respectively, in theantibody-loaded cells. The antibody-loaded cells also showed a 57%increase in insulin stimulated insulin receptor kinase activity towardexogenous peptide substrates.

Kennedy et al., 1999, Science 283: 1544-1548 showed that proteintyrosine phosphatase PTP-1B is a negative regulator of the insulinsignaling pathway, indicating that inhibitors of this enzyme arebeneficial in the treatment of Type 2 diabetes, which appears to involvea defect in an early process in insulin signal transduction rather thana structural defect in the insulin receptor itself. (J. M. Olefsky, W.T. Garvey, R. R. Henry, D. Brillon, S. Matthai and G. R. Freidenberg, G.R. (1988).) Cellular mechanisms of insulin resistance innon-insulin-dependent (Type II) diabetes. (Am. J. Med. 85: Suppl. 5A,86-105.) A drug that improved insulin sensitivity would have severaladvantages over traditional therapy of NIDDM using sulfonylureas, whichdo not alleviate insulin resistance but instead compensate by increasinginsulin secretion.

Therefore, inhibitors of PTP-1B are useful in controlling or treatingType 2 diabetes, in improving glucose tolerance, and in improvinginsulin sensitivity in patients in need thereof.

The compounds are also useful in treating or controlling other PTP-1Bmediated diseases, such as the treatment of cancer, neurodegenerativediseases and the like.

SUMMARY OF THE INVENTION

In a broad aspect, the invention encompasses the compounds of formula(I) shown below, pharmaceutical compositions containing the compoundsand methods employing such compounds or compositions in the treatment ofdiabetes.

In one aspect, the invention encompasses compounds of formula I:

and pharmaceutically acceptable salts thereof, wherein

-   n is 0, 1, 2, 3, or 4;-   R₁ is H, C₁-C₆ alkyl, phenyl(C₁-C₆)alkyl, or C₃-C₆ alkenyl;-   R₂ is phenyl, phenyl(C₁-C₄) alkyl, C₁-C₆ alkyl, —(C₁-C₄)    alkyl-C(O)NH₂, —(C₁-C₄) alkyl-C(O)NH(C₁-C₄)alkyl, —(C₁-C₄)    alkyl-C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, —(C₁-C₄) alkyl-S(O)_(b)—(C₁-C₄)    alkyl, (C₁-C₄) hydroxyalkyl, —(C₁-C₄) alkyl-heterocycloalkyl,    wherein the heterocycloalkyl group is optionally fused to a phenyl    ring and wherein the heterocycloalkyl portion, the phenyl portion,    or both are optionally substituted with a total of 1, 2, 3, or 4    groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy,    —SO₂—(C₁-C₄) alkyl, haloalkyl, or haloalkoxy;    -   wherein b is 0, 1, or 2;-   R₂₀, R₂₁, R₂₂, and R₂₃ are independently selected from H,    arylalkoxy, arylalkyl, halogen, alkyl, haloalkyl, OH, alkoxy, NO₂,    NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆alkyl) (C₁-C₆alkyl), NH-aryl,    NHC(O)—(C₁-C₄) alkyl-aryl, N(C₁-C₄ alkyl)C(O)—(C₁-C₄)alkyl-aryl,    N(C₁-C₄)alkyl-aryl, —NHSO₂-aryl, —N(C₁-C₄alkyl)SO₂aryl, wherein the    aryl group is optionally substituted with 1, 2, 3, or 4 groups that    are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, OH, NO₂,    haloalkyl, haloalkoxy;-   L is —SO₂NH—, —SO₂N(C₁-C₄) alkyl-, —NHSO₂—, —N(C₁-C₄ alkyl)SO₂—, O,    —C(O)NH—, —C(O)N(C₁-C₄)alkyl-, —SO₂—, —C(O)—(C₁-C₄) alkyl-, —(C₁-C₄)    alkyl-C(O)—, —NH—, —(C₁-C₆ alkyl)-O—N═, or —N(C₁-C₄ alkyl)-, wherein    the alkyl group is optionally substituted with phenyl, wherein the    phenyl is optionally substituted with 1, 2, 3, or 4 groups that are    independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, OH, NO₂,    haloalkyl, or haloalkoxy;-   L₃ is a bond, absent, —(C₁-C₄)alkyl-O—, —O—(C₁-C₄)alkyl, —(C₁-C₄)    alkyl-, —C(O)—, —C(O)NH—, or —C(O)N(C₁-C₄ alkyl)-;-   the A-ring is aryl selected from the group consisting of phenyl,    naphthyl and fluorenyl, or heteroaryl, each of which is optionally    substituted with 1, 2, or 3 groups that are independently, halogen,    C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, NO₂,    NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆) alkyl (C₁-C₆) alkyl;-   Q is H, aryl, heteroaryl, -heteroaryl-alkyl, -aryl-heteroaryl,    aryl-C(O)-aryl, aryl-(C₁-C₄ alkyl)-aryl, heteroaryl-(C₁-C₄    alkyl)-aryl, -heteroaryl-aryl, wherein the aryl group is a phenyl,    naphthyl, or fluorenyl, each of which is optionally substituted with    1, 2, 3, or 4 groups that are independently C₁-C₆ alkyl, C₁-C₄    alkoxycarbonyl, C₁-C₆ alkoxy, halogen, haloalkyl, haloalkoxy, NR₆R₇,    or phenyl; wherein    -   R₆ and R₇ are independently H, C₁-C₆ alkyl, aryl(C₁-C₆)alkyl,        alkanoyl, arylalkanoyl, alkoxycarbonyl, arylalkoxycarbonyl,        heteroarylcarbonyl, heteroaryl, heterocycloalkylcarbonyl,        —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl, —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl,        or —SO₂-aryl, wherein the cyclic groups are optionally        substituted with 1, 2, 3, or 4 groups that are independently        halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, NO₂, OH, NH₂,        NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, haloalkyl or        haloalkoxy.

Compounds of formula I bind to PTP-1B. Preferably that interactionresults in inhibition of the enzyme.

The invention also includes intermediates that are useful in making thecompounds of the invention.

The invention also provides pharmaceutical compositions comprising acompound or salt of formula I and at least one pharmaceuticallyacceptable carrier, solvent, adjuvant or diluent.

The invention further provides methods of treating disease in a patientin need of such treatment, comprising administering a compound orpharmaceutically acceptable salt of formula I, or a pharmaceuticalcomposition comprising a compound or salt of formula I.

In another aspect, the invention provides a method for inhibitingprotein tyrosine phosphatase comprising administering a therapeuticallyeffective amount of a compound of formula I.

In another aspect, the invention provides a method for treatingmetabolic disorders related to insulin resistance or hyperglycemia,comprising administering a therapeutically effective amount of acompound of formula I.

The invention also provides the use of a compound or salt according toformula I for the manufacture of a medicament.

The invention also provides methods of preparing the compounds of theinvention and the intermediates used in those methods.

The invention also provides methods and compositions for combinationtherapy of Type I and Type II diabetes. In these embodiments, theinvention provides formulations and pharmaceutical compositions, as wellas methods for treating Type I and Type II diabetes with the PTPaseinhibitors of formula I plus additional compounds and medicaments asdisclosed in more detail below. In these embodiments, the methods of theinvention can comprise treatment methods for Type I and Type II diabeteswhere the PTPase inhibitors of formula I are formulated with atherapeutically-effective amount of said additional compounds andmedicaments. In alternative embodiments, treatment methods of theinvention for Type I and Type II diabetes comprise administration of theinventive PTPase inhibitors of formula I as disclosed hereinconcomitantly, simultaneously or together with atherapeutically-effective amount of said additional compounds andmedicaments.

DETAILED DESCRIPTION OF THE INVENTION

A preferred class of compounds of formula I are compounds of formulaI-a, wherein,

-   R₂ is phenyl, phenyl(C₁-C₄) alkyl (such as benzyl, or phenethyl),    C₁-C₆ alkyl (such as methyl, ethyl, isopropyl, isopropyl, or    pentyl), —(C₁-C₄) alkyl-C(O)NH₂, —(C₁-C₄) alkyl-C(O)NH(C₁-C₄) alkyl,    —(C₁-C₄) alkyl-C(O)N(C₁-C₄)alkyl(C₁-C₄) alkyl, —(C₁-C₄)    alkyl-S(O)_(b)—(C₁-C₄) alkyl, (C₁-C₄) hydroxyalkyl, —(C₁-C₄)    alkyl-phthalimidyl, —(C₁-C₄) alkyl-piperidinyl, —(C₁-C₄)    alkyl-pyrrolidinyl, —(C₁-C₄) alkyl-morpholinyl, wherein the    phthalimidyl, piperidinyl, pyrrolidinyl, or morpholinyl groups are    optionally fused to a phenyl ring and wherein said phthalimidyl,    piperidinyl, pyrrolidinyl, or morpholinyl groups are, the phenyl    portion, or both are optionally substituted with a total of 1, 2, 3,    or 4 groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄    alkoxy, —SO₂—(C₁-C₄) alkyl (C₁-C₄)haloalkyl, or (C₁-C₄)haloalkoxy;    wherein b is 0, 1, or 2;    -   and-   Q is H, pyrido[1,2-a]indolyl, indolyl, isoindolyl, indolizinyl,    imidazo[1,2-a]pyridine, -phenyl-C(O)-phenyl, -phenyl-(C₁-C₄)    alkyl-phenyl, -pyridyl-phenyl, fluorenyl, -fluorenyl-pyridyl,    -fluorenyl-phenyl, -benzofuranyl-(C₁-C₄) alkyl-phenyl,    -benzimidazolyl-(C₁-C₄) alkyl-phenyl, benzoxazolyl-(C₁-C₄)    alkyl-phenyl, indolizinyl, benzofuranyl,    -indolyl-(C₁-C₄)alkyl-phenyl, -phenyl-benzoxazolyl, benzo[b]thienyl,    dibenzo[b,d]furan, phenyl, or dibenzothienyl, each of which is    optionally substituted with 1, 2, 3, or 4 groups that are    independently C₁-C₆ alkyl, C₁-C₄ alkoxycarbonyl, C₁-C₆ alkoxy,    halogen, haloalkyl, haloalkoxy, NR₆R₇, or phenyl; wherein    -   R₆ and R₇ are independently H, C₁-C₆ alkyl, aryl(C₁-C₆)alkyl,        alkanoyl, phenyl(C₁-C₄)alkanoyl, alkoxycarbonyl,        phenyl(C₁-C₄)alkoxycarbonyl, pyridylcarbonyl, pyridyl,        piperidinyl, pyrrolidinylcarbonyl, —C(O)NH₂,        —C(O)NH(C₁-C₆)alkyl, —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, or        —SO₂-phenyl, wherein the cyclic groups are optionally        substituted with 1, 2, 3, or 4 groups that are independently        halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, NO₂, OH, NH₂,        NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, CF₃ or OCF₃.

Particularly preferred compounds of formula I are those where R₁ is H.Compounds of formula I having R₁ groups that are C₁-C₆ alkyl, benzyl andallyl are preferred as intermediates.

A preferred class of compounds of formula I-a are compounds of formulaI-b, wherein,

-   the A-ring is selected from phenyl, naphthyl, pyridyl, benzofuranyl,    dibenzofuranyl, pyrrolyl, furanyl, isoindolyl, or indolyl each of    which is optionally substituted with 1, 2, or 3 groups that are    independently, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,    C₁-C₄ haloalkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl, or N(C₁-C₆)alkyl(C₁-C₆)    alkyl; and-   R₂₀, R₂₁, R₂₂, and R₂₃ are independently selected from H,    phenylalkoxy, phenylalkyl, halogen, alkyl, OH, alkoxy, NO₂, NH₂,    NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, NH-phenyl, NHC(O)—(C₁-C₄)    alkyl-phenyl, N(C₁-C₄ alkyl)C(O)—(C₁-C₄) alkyl-phenyl,    N(C₁-C₄)alkyl-phenyl, —NHSO₂-phenyl, or —N(C₁-C₄alkyl)SO₂phenyl,    wherein the phenyl groups are optionally substituted with 1, 2, 3,    or 4 groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy,    halogen, OH, NO₂, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy.

A preferred class of compounds of formula I-b are compounds of formulaI-c, wherein,

-   L is —SO₂NH—, —SO₂N(C₁-C₄ alkyl)-, —NHSO₂, O, —C(O)NH—,    —C(O)N(C₁-C₄)alkyl-, —SO₂—, —C(O)—(C₁-C₄) alkyl-, —(C₁-C₄)    alkyl-C(O)—, —NH—, —N(C₁-C₄ alkyl)-, wherein the alkyl group is    optionally substituted with phenyl, which is optionally substituted    with 1, 2, 3, or 4 groups that are independently C₁-C₆ alkyl, C₁-C₆    alkoxy, halogen, OH, NO₂, C₁-C₄ haloalkyl, or C₁-C₄ haloalkoxy.

A preferred class of compounds of formula I-c are compounds of formulaI-d, wherein,

-   the A-ring is selected from naphthyl, benzofuranyl, dibenzofuranyl,    isoindolyl, or indolyl each of which is optionally substituted with    1, 2, or 3 groups that are independently, halogen, C₁-C₄ alkyl,    C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, NO₂, NH₂,    NH(C₁-C₆)alkyl, or N(C₁-C₆) alkyl (C₁-C₆) alkyl.

A preferred class of compounds of formula I-d are compounds of formulaI-e,

-   the A-ring is benzofuranyl, dibenzofuranyl, or indolyl each of which    is optionally substituted with 1, 2, or 3 groups that are    independently, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,    C₁-C₄ haloalkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl, or N(C₁-C₆) alkyl    (C₁-C₆) alkyl.

A preferred class of compounds of formula I-e are compounds of formulaI-f,

-   the A-ring is indolyl which is optionally substituted with 1, 2, or    3 groups that are independently, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy,    CF₃, OCF₃, NO₂, NH₂, NH(C₁-C₆)alkyl, or N(C₁-C₆) alkyl (C₁-C₆)    alkyl.

A preferred class of compounds of formula I-c are compounds of formulaI-g,

-   the A-ring is selected from pyridyl, pyrrolyl, or furanyl, each of    which is optionally substituted with 1, 2, or 3 groups that are    independently, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,    C₁-C₄ haloalkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl, or N(C₁-C₆) alkyl    (C₁-C₆)alkyl.

A preferred class of compounds of formulas I-d, 1-e, 1-f, or I-g, arecompounds of formula I-h, wherein

-   L₃ is a bond, absent, —(C₁-C₄)alkyl-O—, —O—(C₁-C₄)alkyl, —(C₁-C₄)    alkyl-, or —C(O)—; and-   Q is H, pyrido[1,2-a]indolyl, indolyl, imidazo[1,2-a]pyridine,    -phenyl-C(O)-phenyl, -phenyl-(C₁-C₄) alkyl-phenyl, fluorenyl,    -benzofuranyl-(C₁-C₄) alkyl-phenyl, indolizinyl, benzofuranyl,    -indolyl-(C₁-C₄)alkyl-phenyl, -phenyl-benzoxazolyl, benzo[b]thienyl,    dibenzo[b,d]furan, phenyl, or dibenzothienyl, each of which is    optionally substituted with 1, 2, 3, or 4 groups that are    independently C₁-C₆ alkyl, C₁-C₄ alkoxycarbonyl, C₁-C₆ alkoxy,    halogen, haloalkyl, haloalkoxy, NR₆R₇, or phenyl.

A preferred class of compounds of formula I-h are compounds of formulaI-i,

-   L₃ is a bond, —O—(C₁-C₄)alkyl-, or —(C₁-C₄) alkyl-; and-   Q is H, pyrido[1,2-a]indolyl, indolyl, -phenyl-C(O)-phenyl,    -benzofuranyl-(C₁-C₄) alkyl-phenyl, indolizinyl, or benzofuranyl,    each of which is optionally substituted with 1, 2, 3, or 4 groups    that are independently C₁-C₆ alkyl, C₁-C₄ alkoxycarbonyl, C₁-C₆    alkoxy, halogen, haloalkyl, haloalkoxy, NR₆R₇, or phenyl.

A preferred class of compounds of formula I-i are compounds of formulaI-j,

-   R₂ is phenyl, phenyl(C₁-C₄) alkyl(such as benzyl or phenethyl) C₁-C₆    alkyl (methyl, ethyl, isopropyl, isopropyl, isobutyl, or pentyl),    —(C₁-C₄) alkyl-C(O)NH₂, —(C₁-C₄) alkyl-S(O)_(b)—(C₁-C₄) alkyl,    (C₁-C₄) hydroxyalkyl, wherein the phenyl groups are optionally    substituted with 1, 2, 3, or 4 groups that are independently    halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, —SO₂—(C₁-C₄) alkyl, CF₃ or OCF₃.

A preferred class of compounds of formula I-j are compounds of formulaI-k, wherein

-   R₁ is H, or C₁-C₆ alkyl; and-   R₂₀, R₂₁, R₂₂, and R₂₃ are independently selected from H, halogen,    alkyl, OH, alkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆alkyl)    (C₁-C₆alkyl), NH-phenyl, or NHC(O)—(C₁-C₄) alkyl-phenyl, wherein the    phenyl group is optionally substituted with 1, 2, 3, or 4 groups    that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, OH, NO₂,    CF₃, or OCF₃.

A preferred class of compounds of formula I-k are compounds of formulaI-l, wherein

-   n is 0 or 1;-   R₁ is H;-   R₂₂ and R₂₃ are both hydrogen; and-   R₂₀, and R₂₁, are independently selected from H, halogen, alkyl, OH,    alkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl, or N(C₁-C₆alkyl) (C₁-C₆alkyl).

A preferred class of compounds of formula I-l are compounds of formulaI-m, wherein

-   R₆ is hydrogen; and-   R₇ is H, C₁-C₆ alkyl, benzyl, phenethyl, C₂-C₆ alkanoyl,    phenyl(C₁-C₄) alkanoyl, C₁-C₄alkoxycarbonyl, phenyl(C₁-C₄)    alkoxycarbonyl, pyridylcarbonyl, pyridyl, piperidinyl,    pyrrolidinylcarbonyl, or —SO₂-phenyl, wherein the cyclic groups are    optionally substituted with 1, 2, 3, or 4 groups that are    independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, NO₂, OH, NH₂,    NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, CF₃ or OCF₃.

A preferred class of compounds of formula I-m are compounds of formulaI-n, wherein

-   R₂ is phenyl, phenyl(C₁-C₄) alkyl(such as benzyl, phenethyl), or    C₁-C₆ alkyl (such as methyl, ethyl, propyl, isopropyl, isobutyl, or    pentyl), wherein the phenyl groups are optionally substituted with    1, 2, 3, or 4 groups that are independently halogen, C₁-C₄ alkyl,    C₁-C₄ alkoxy, —SO₂—(C₁-C₄) alkyl, CF₃ or OCF₃.

A preferred class of compounds of formula I-n are compounds of formulaI-o, wherein

-   R₂ is phenyl, wherein the phenyl group is optionally substituted    with 1, 2, 3, or 4 groups that are independently halogen, C₁-C₄    alkyl, C₁-C₄ alkoxy, —SO₂—(C₁-C₄) alkyl, CF₃ or OCF₃.

A preferred class of compounds of formula I-o are compounds of formulaI-p, wherein

-   R₂ is phenyl(C₁-C₄) alkyl(such as benzyl or phenethyl), wherein the    phenyl groups are optionally substituted with 1, 2, 3, or 4 groups    that are independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy,    —SO₂—(C₁-C₄) alkyl, CF₃ or OCF₃. In another aspect, the    phenyl(C₁-C₄) alkyl is benzyl or phenethyl.

A preferred class of compounds of formula I-n are compounds of formulaI-q, wherein

R₂ is C₁-C₆ alkyl (such as methyl, ethyl, isopropyl, isobutyl orpentyl).

In another aspect, the C₁-C₆ alkyl is methyl, ethyl, isopropyl, orisobutyl.

A preferred class of compounds of formula I-m are compounds of formulaI-r, wherein

-   R₂ is —(C₁-C₄) alkyl-C(O)NH₂, —(C₁-C₄) alkyl-S(O)_(b)—(C₁-C₄) alkyl,    -   or (C₁-C₄) hydroxyalkyl, wherein    -   b is 0, 1 or 2.

A Preferred class of compounds of formula I-c include compounds offormula II:

wherein

-   R₁ is H or C₁-C₆ alkyl (preferably R₁ is H);-   R₂ is phenyl, phenyl(C₁-C₄) alkyl(such as benzyl, phenethyl) C₁-C₆    alkyl (such as methyl, ethyl, isopropyl, isobutyl, pentyl), —(C₁-C₄)    alkyl-C(O)NH₂, —(C₁-C₄) alkyl-S(O)_(b)—(C₁-C₄) alkyl, or (C₁-C₄)    hydroxyalkyl, wherein the phenyl groups are optionally substituted    with 1, 2, 3, or 4 groups that are independently halogen, C₁-C₄    alkyl, C₁-C₄ alkoxy, —SO₂—(C₁-C₄) alkyl, (C₁-C₄)haloalkyl (such as    CF₃), or (C₁-C₄)haloalkoxy (such as OCF₃);-   v is 0, 1, 2, 3, or 4;-   R₁₀ at each occurrence is independently halogen, C₁-C₄ alkyl, C₁-C₄    alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl,    or N(C₃-C₆)alkyl(C₁-C₆)alkyl; and-   L₃ is a bond, absent, —O—(C₁-C₄)alkyl, —(C₁-C₄) alkyl-, or —C(O)—.

A Preferred class of compounds of formula II include compounds offormula II-a, wherein

-   Q is H, pyrido[1,2-a]indolyl, indolyl, imidazo[1,2-a]pyridine,    -phenyl-C(O)-phenyl, -phenyl-(C₁-C₄) alkyl-phenyl, fluorenyl,    -benzofuranyl-(C₁-C₄) alkyl-phenyl, indolizinyl, benzofuranyl,    -indolyl-(C₁-C₄)alkyl-phenyl, -phenyl-benzoxazolyl, benzo[b]thienyl,    dibenzo[b,d]furan, phenyl, or dibenzothienyl, each of which is    optionally substituted with 1, 2, 3, or 4 groups that are    independently C₁-C₆ alkyl, C₁-C₄ alkoxycarbonyl, C₁-C₆ alkoxy,    halogen, haloalkyl, haloalkoxy, NR₆R₇, or phenyl; wherein    -   R₆ and R₇ are independently H, C₁-C₆ alkyl, aryl(C₁-C₆)alkyl,        alkanoyl, phenyl(C₁-C₄)alkanoyl, alkoxycarbonyl,        phenyl(C₃-C₄)alkoxycarbonyl, pyridylcarbonyl, pyridyl,        pyrrolidinylcarbonyl, or —SO₂-phenyl, wherein the cyclic groups        are optionally substituted with 1, 2, 3, or 4 groups that are        independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, NO₂, OH, NH₂,        NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, CF₃ or OCF₃.

A Preferred class of compounds of formula II-a include compounds offormula II-b, wherein

-   R₂ is phenyl, phenyl(C₁-C₄) alkyl (such as benzyl or phenethyl), or    (C₁-C₆)alkyl, wherein the phenyl groups are optionally substituted    with 1, 2, 3, or 4 groups that are independently halogen, C₁-C₄    alkyl, C₁-C₄ alkoxy, or —SO₂—(C₁-C₄) alkyl, CF₃ or OCF₃; and-   R₂₀, R₂₁, R₂₂, and R₂₃ are independently selected from H, halogen,    alkyl, OH, alkoxy, NO₂, NH₂, NH(C₃-C₆)alkyl, or N(C₁-C₆alkyl)    (C₁-C₆alkyl).

A Preferred class of compounds of formula II-b include compounds offormula II-c, wherein

-   R₂₂ and R₂₃ are both hydrogen.

A Preferred class of compounds of formula II-c include compounds offormula II-d, wherein

-   R₁ and R₆ are hydrogen; and-   v is 0 or 1.

A Preferred class of compounds of formula II-b include compounds offormula II-e, wherein

-   L₃ is a bond, —O—(C₁-C₄)alkyl, —(C₁-C₄) alkyl-, or —C(O)—;-   Q is indolyl, -phenyl-C(O)-phenyl, -benzofuranyl-(C₁-C₄)    alkyl-phenyl, indolizinyl, benzofuranyl, -indolyl-(C₁-C₄)    alkyl-phenyl, benzo[b]thienyl, dibenzo[b,d]furan, phenyl, or    dibenzothienyl, each of which is optionally substituted with 1, 2,    3, or 4 groups that are independently C₁-C₆ alkyl, C₁-C₄    alkoxycarbonyl, C₁-C₆ alkoxy, halogen, haloalkyl, haloalkoxy, NR₆R₇,    or phenyl; wherein    -   R₆ and R₇ are independently H, C₁-C₆ alkyl, phenyl(C₁-C₆)alkyl,        alkanoyl, phenyl(C₁-C₄)alkanoyl, alkoxycarbonyl,        pyridylcarbonyl, pyridyl, pyrrolidinylcarbonyl, or —SO₂-phenyl,        wherein the cyclic groups are optionally substituted with 1, 2,        3, or 4 groups that are independently halogen, C₁-C₄ alkyl,        C₁-C₄ alkoxy, NO₂, OH, NH₂, NH(C₁-C₆)alkyl,        N(C₁-C₆)alkyl(C₁-C₆)alkyl, CF₃ or OCF₃.

A Preferred class of compounds of formula II-e include compounds offormula III

A Preferred class of compounds of formula III include compounds offormula III-a, wherein

-   L is —SO₂NH—, —SO₂N(C₁-C₄ alkyl)-, or —SO₂— wherein the alkyl group    is optionally substituted with phenyl, which is optionally    substituted with 1, 2, 3, or 4 groups that are independently C₁-C₆    alkyl, C₁-C₆ alkoxy, halogen, OH, NO₂, C₁-C₄ haloalkyl, or C₁-C₄    haloalkoxy.

A Preferred class of compounds of formula III-a include compounds offormula III-b, wherein

-   R₁ is H;-   R₂₁ is H, NO₂, C₁-C₆ alkyl, or halogen; and-   R₂ is phenyl, benzyl, or (C₁-C₆)alkyl, wherein each phenyl group is    optionally substituted with 1, 2, 3, or 4 groups that are    independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, or —SO₂—(C₁-C₄)    alkyl, CF₃ or OCF₃.

A Preferred class of compounds of formula III-b include compounds offormula III-c, wherein

-   L is —SO₂NH—, or —SO₂N(C₁-C₄ alkyl)- wherein the alkyl group is    optionally substituted with phenyl, which is optionally substituted    with 1, 2, 3, or 4 groups that are independently C₁-C₆ alkyl, C₁-C₆    alkoxy, halogen, OH, NO₂, C₁-C₄ haloalkyl, or C₁-C₄ haloalkoxy.

A Preferred class of compounds of formula III-c include compounds offormula III-d, wherein

-   L is —SO₂N(C₁-C₄ alkyl)-.

A Preferred class of compounds of formula III-c include compounds offormula III-e, wherein

-   L is —SO₂N(C₁-C₄ alkyl)- wherein the alkyl group is substituted with    phenyl, which is optionally substituted with 1, 2, 3, or 4 groups    that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, OH, NO₂,    CF₃ or OCF₃.

A Preferred class of compounds of formula III-c include compounds offormula III-f, wherein

-   L is —SO₂NH—.

A Preferred class of compounds according to any one of formulas III-b,III-c, III-d, or III-e, include compounds of formula III-g, wherein

-   R₂ is phenyl or benzyl, each of which is substituted at position    number 3 or 4 of the R₂ phenyl ring with a halogen, CF₃ or OCF₃.

A Preferred class of compounds according to any one of formulas III-b,III-c, III-d, or III-e, include compounds of formula III-h, wherein

-   R₂ is C₁-C₆ alkyl.

A Preferred class of compounds of formula III-b include compounds offormula III-i, wherein

-   L₃ is a bond, —O—(C₁-C₄)alkyl, or —(C₁-C₄) alkyl-;-   Q is -benzofuranyl-(C₁-C₄) alkyl-phenyl, indolizinyl, benzofuranyl,    dibenzo[b,d]furan, or dibenzothienyl, each of which is optionally    substituted with 1, 2, 3, or 4 groups that are independently C₁-C₆    alkyl, C₁-C₄ alkoxycarbonyl, C₁-C₆ alkoxy, halogen, haloalkyl,    haloalkoxy, NR₆R₇, or phenyl; wherein    -   R₆ and R₇ are independently H, C₁-C₆ alkyl, phenyl(C₁-C₆)alkyl,        alkanoyl, phenyl(C₁-C₄)alkanoyl, alkoxycarbonyl,        pyridylcarbonyl, pyridyl, pyrrolidinylcarbonyl, or —SO₂-phenyl,        wherein the cyclic groups are optionally substituted with 1, 2,        3, or 4 groups that are independently halogen, C₁-C₄ alkyl,        C₁-C₄ alkoxy, NO₂, OH, NH₂, NH(C₁-C₆)alkyl,        N(C₃-C₆)alkyl(C₁-C₆)alkyl, CF₃ or OCF₃.

A Preferred class of compounds of formula III-i include compounds offormula III-J, wherein

-   Q is -benzofuranyl-(C₃-C₄) alkyl-phenyl, indolizinyl, benzofuranyl,    dibenzo[b,d]furan, or dibenzothienyl, each of which is optionally    substituted with 1, 2, 3, or 4 groups that are independently C₁-C₆    alkyl, C₁-C₄ alkoxycarbonyl, C₁-C₆ alkoxy, halogen, haloalkyl, or    haloalkoxy.

A Preferred class of compounds of formula III include compounds offormula III-k, wherein

-   L is —O—.

A Preferred class of compounds of formula III-k include compounds offormula III-l, wherein

-   R₁ is H;-   R₂₁ is H, NO₂, C₁-C₆ alkyl, or halogen; and-   R₂ is phenyl, phenyl(C₁-C₄)alkyl, or (C₁-C₆)alkyl, wherein each    phenyl group is optionally substituted with 1, 2, 3, or 4 groups    that are independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, or    —SO₂—(C₁-C₄) alkyl, CF₃ or OCF₃.

A Preferred class of compounds of formula III-l include compounds offormula III-m, wherein

-   R₂ is phenyl or benzyl, wherein each is optionally substituted with    1, 2, 3, or 4 groups that are independently halogen, C₁-C₄ alkyl,    C₁-C₄ alkoxy, —SO₂—(C₁-C₄) alkyl, CF₃ or OCF₃.

A Preferred class of compounds of formula III-m include compounds offormula III-n, wherein

-   R₂ is phenyl or benzyl, each of which is substituted at position    number 3 or 4 of the R₂ phenyl ring with a halogen, CF₃ or OCF₃.

A Preferred class of compounds of formula III-l include compounds offormula III-o, wherein

-   R₂ is phenyl which is substituted at position number 3 or 4 of the    R₂ phenyl ring with a halogen, CF₃ or OCF₃.

A Preferred class of compounds of formula III-l include compounds offormula III-p, wherein

-   R₂ is benzyl, which is substituted at position number 3 or 4 of the    R₂ phenyl ring with a halogen, CF₃ or OCF₃.

A Preferred class of compounds of formula III-l include compounds offormula III-q, wherein

-   R₂ is C₁-C₆ alkyl.

A Preferred class of compounds of formula III-l include compounds offormula III-r, wherein

-   L₃ is a bond, —O—(C₁-C₄)alkyl, or —(C₁-C₄) alkyl-;-   Q is indolyl, -phenyl-C(O)-phenyl, -benzofuranyl-(C₁-C₄)    alkyl-phenyl, indolizinyl, benzofuranyl, or    -indolyl-(C₁-C₄)alkyl-phenyl, each of which is optionally    substituted with 1, 2, 3, or 4 groups that are independently C₁-C₆    alkyl, C₁-C₄ alkoxycarbonyl, C₁-C₆ alkoxy, halogen, haloalkyl,    haloalkoxy, NR₆R₇, or phenyl; wherein    -   R₆ and R₇ are independently H, C₁-C₆ alkyl, phenyl(C₁-C₆)alkyl,        alkanoyl, phenyl(C₁-C₄) alkanoyl, alkoxycarbonyl,        pyridylcarbonyl, pyrrolidinylcarbonyl, or —SO₂-phenyl, wherein        the cyclic groups are optionally substituted with 1, 2, 3, or 4        groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄        alkoxy, NO₂, OH, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl,        CF₃ or OCF₃.

A Preferred class of compounds of formula III-r include compounds offormula III-s, wherein

-   Q is indolyl, -phenyl-C(O)-phenyl, -benzofuranyl-(C₁-C₄)    alkyl-phenyl, indolizinyl, benzofuranyl, or    -indolyl-(C₁-C₄)alkyl-phenyl.

A Preferred class of compounds of formula III include compounds offormula III-t, wherein

-   L is —C(O)NH—, —C(O)N(C₁-C₄)alkyl-, —C(O)—(C₁-C₄) alkyl-, —NH—, or    —N(C₁-C₄) alkyl-, wherein the alkyl groups are optionally    substituted with phenyl, which is optionally substituted with 1, 2,    3, or 4 groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy,    halogen, OH, NO₂, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy.

A Preferred class of compounds of formula III-l include compounds offormula III-u, wherein

-   L is —C(O)NH—, or —C(O)N(C₁-C₄)alkyl-;-   R₁ is H;-   R₂₁ is H, NO₂, C₁-C₆ alkyl, or halogen.

A Preferred class of compounds of formula III-u include compounds offormula III-v, wherein

-   R₂ is phenyl, phenyl(C₁-C₄)alkyl, or (C₁-C₆)alkyl, wherein each    phenyl group is optionally substituted with 1, 2, 3, or 4 groups    that are independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, or    —SO₂—(C₁-C₄) alkyl, CF₃ or OCF₃.

A Preferred class of compounds of formula III-v include compounds offormula III-w, wherein

-   R₂ is phenyl or benzyl, wherein each is optionally substituted with    1, 2, 3, or 4 groups that are independently halogen, C₁-C₄ alkyl,    C₁-C₄ alkoxy, —SO₂—(C₁-C₄) alkyl, CF₃ or OCF₃.

A Preferred class of compounds of formula III-m include compounds offormula III-x, wherein

-   R₂ is phenyl or benzyl, each of which is substituted at position    number 3 or 4 of the R₂ phenyl ring with a halogen, CF₃ or OCF₃.

A Preferred class of compounds of formula III-l include compounds offormula III-y, wherein

-   R₂ is phenyl which is substituted at position number 3 or 4 of the    R₂ phenyl ring with a halogen, CF₃ or OCF₃.

A Preferred class of compounds of formula III-l include compounds offormula III-z, wherein

-   R₂ is benzyl, each of which is substituted at position number 3 or 4    of the R₂ phenyl ring with a halogen, CF₃ or OCF₃.

A Preferred class of compounds of formula III-l include compounds offormula III-aa, wherein

-   R₂ is C₁-C₆ alkyl.

A Preferred class of compounds of formula III-v include compounds offormula III-bb, wherein

-   L₃ is a bond, —O—(C₁-C₄)alkyl, or —(C₁-C₄) alkyl-;-   Q is indolyl, -phenyl-C(O)-phenyl, -benzofuranyl-(C₁-C₄)    alkyl-phenyl, indolizinyl, benzofuranyl, or    -indolyl-(C₁-C₄)alkyl-phenyl, each of which is optionally    substituted with 1, 2, 3, or 4 groups that are independently C₁-C₆    alkyl, C₁-C₄ alkoxycarbonyl, C₁-C₆ alkoxy, halogen, haloalkyl,    haloalkoxy, NR₆R₇, or phenyl; wherein    -   R₆ and R₇ are independently H, C₁-C₆ alkyl, phenyl(C₁-C₆)alkyl,        alkanoyl, phenyl(C₁-C₄)alkanoyl, alkoxycarbonyl,        pyridylcarbonyl, pyrrolidinylcarbonyl, or —SO₂-phenyl, wherein        the cyclic groups are optionally substituted with 1, 2, 3, or 4        groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄        alkoxy, NO₂, OH, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl,        CF₃ or OCF₃.

A Preferred class of compounds of formula III-bb include compounds offormula III-cc, wherein

-   L₃ is a bond, or —(C₁-C₄) alkyl-; and-   Q is indolyl, -phenyl-C(O)-phenyl, -benzofuranyl-(C₁-C₄)    alkyl-phenyl, indolizinyl, or benzofuranyl, each of which is    optionally substituted with 1, 2, 3, or 4 groups that are    independently C₁-C₆ alkyl, C₁-C₄ alkoxycarbonyl, C₁-C₆ alkoxy,    halogen, haloalkyl, haloalkoxy, NR₆R₇, or phenyl.

A Preferred class of compounds of formula III-cc include compounds offormula III-dd, wherein

-   Q is -benzofuranyl-(C₁-C₄) alkyl-phenyl, indolizinyl, or    benzofuranyl.

A Preferred class of compounds of formula II include compounds offormula II-f, wherein

-   L is —NH—, or —N(C₁-C₄) alkyl-.

A Preferred class of compounds of formula II-f include compounds offormula II-g, wherein

-   R₁ is H;-   R₂₁ is H, NO₂, C₁-C₆ alkyl, or halogen; and-   R₂ is phenyl, phenyl(C₁-C₄) alkyl(such as benzyl or phenethyl),    C₁-C₆ alkyl (such as methyl, ethyl, isopropyl), —(C₁-C₄)    alkyl-C(O)NH₂, —(C₁-C₄) alkyl-S(O)_(b)—(C₁-C₄) alkyl, or (C₁-C₄)    hydroxyalkyl, wherein the phenyl groups are optionally substituted    with 1, 2, 3, or 4 groups that are independently halogen, C₁-C₄    alkyl, C₁-C₄ alkoxy, —SO₂—(C₁-C₄) alkyl, CF₃ or OCF₃.

A Preferred class of compounds of formula II-g include compounds offormula II-h, wherein

-   L₃ is a bond, —O—(C₁-C₄)alkyl, or —(C₁-C₄) alkyl-;-   Q is indolyl, -phenyl-C(O)-phenyl, -benzofuranyl-(C₁-C₄)    alkyl-phenyl, indolizinyl, benzofuranyl, or    -indolyl-(C₁-C₄)alkyl-phenyl, each of which is optionally    substituted with 1, 2, 3, or 4 groups that are independently C₁-C₆    alkyl, C₁-C₄ alkoxycarbonyl, C₁-C₆ alkoxy, halogen, haloalkyl,    haloalkoxy, NR₆R₇, or phenyl; wherein    -   R₆ and R₇ are independently H, C₁-C₆ alkyl, phenyl(C₁-C₆)alkyl,        alkanoyl, phenyl(C₁-C₄)alkanoyl, alkoxycarbonyl,        pyridylcarbonyl, pyrrolidinylcarbonyl, or —SO₂-phenyl, wherein        the cyclic groups are optionally substituted with 1, 2, 3, or 4        groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄        alkoxy, NO₂, OH, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl,        CF₃ or OCF₃.

A Preferred class of compounds of formula II-h include compounds offormula II-i, wherein

-   L₃ is a bond, or —(C₁-C₄) alkyl-; and-   Q is indolyl, -benzofuranyl-(C₁-C₄) alkyl-phenyl, indolizinyl,    benzofuranyl, or -indolyl-(C₁-C₄)alkyl-phenyl, each of which is    optionally substituted with 1, 2, 3, or 4 groups that are    independently C₁-C₆ alkyl, C₁-C₄ alkoxycarbonyl, C₁-C₆ alkoxy,    halogen, CF₃ or OCF₃.

A Preferred class of compounds of formula II-i include compounds offormula II-j, wherein

-   R₂ is —(C₁-C₄) alkyl-C(O)NH₂, —(C₁-C₄) alkyl-S(O)_(b)—(C₁-C₄) alkyl,    or (C₁-C₄) hydroxyalkyl.

A Preferred class of compounds of formula II-i include compounds offormula II-k, wherein

-   R₂ is —(C₁-C₄) alkyl-C(O)NH₂.

A Preferred class of compounds of formula II-i include compounds offormula II-1, wherein

-   R₂ is —(C₁-C₄) alkyl-S(O)_(b)—(C₁-C₄) alkyl.

A Preferred class of compounds of formula II-i include compounds offormula II-m, wherein

-   R₂ is (C₁-C₄) hydroxyalkyl.

A Preferred class of compounds of formulas I-h, II-i, II-j. II-k, II-l,or II-m include compounds of formula II-n, wherein

-   R₂ is phenyl, phenyl(C₁-C₄)alkyl, or (C₁-C₆)alkyl, wherein each    phenyl group is optionally substituted with 1, 2, 3, or 4 groups    that are independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, or    —SO₂—(C₁-C₄) alkyl, CF₃ or OCF₃.

A Preferred class of compounds of formula II-n include compounds offormula II-o, wherein

-   R₂ is phenyl or benzyl, wherein each is optionally substituted with    1, 2, 3, or 4 groups that are independently halogen, C₁-C₄ alkyl,    C₁-C₄ alkoxy, —SO₂—(C₁-C₄) alkyl, CF₃ or OCF₃.

A Preferred class of compounds of formula II-o include compounds offormula II-p, wherein

-   R₂ is phenyl or benzyl, each of which is substituted at position    number 3 or 4 of the R₂ phenyl ring with a halogen, CF₃ or OCF₃.

A Preferred class of compounds of formula II-p include compounds offormula II-q, wherein

-   R₂ is phenyl which is substituted at position number 3 or 4 of the    R₂ phenyl ring with a halogen, CF₃ or OCF₃.

Another Preferred class of compounds of formula II-o include compoundsof formula II-r, wherein

-   R₂ is benzyl, which is substituted at position number 3 or 4 of the    R₂ phenyl ring with a halogen, CF₃ or OCF₃.

A Preferred class of compounds of formula II-n include compounds offormula II-s, wherein

-   R₂ is C₁-C₆ alkyl.

Another preferred class of compounds of formula I-a include compounds offormula IV, wherein

wherein

-   v is 0, 1, 2, 3, or 4;-   R₁₀ at each occurrence is independently halogen, C₁-C₄ alkyl, C₁-C₄    alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl,    or N(C₁-C₆)alkyl(C₁-C₆)alkyl; and-   L is —C(O)—(C₁-C₄) alkyl-, —(C₁-C₄) alkyl-C(O)—, wherein the alkyl    groups are optionally substituted with phenyl, which is optionally    substituted with 1, 2, 3, or 4 groups that are independently C₁-C₆    alkyl, C₁-C₆ alkoxy, halogen, OH, NO₂, C₁-C₄ haloalkyl, or C₁-C₄    haloalkoxy.

A Preferred class of compounds of formula IV include compounds offormula IV-a, wherein

-   R₁ is H;-   R₂₀, R₂₂, and R₂₃ are independently selected from H, halogen, alkyl,    OH, alkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl, or N(C₁-C₆alkyl) (C₁-C₆alkyl);-   R₂₁ is H, NO₂, C₁-C₆ alkyl, or halogen; and-   R₂ is phenyl, phenyl(C₁-C₄) alkyl(such as benzyl or phenethyl),    C₁-C₆ alkyl (such as methyl, ethyl, isopropyl, isobutyl), —(C₁-C₄)    alkyl-phthalimidyl, —(C₁-C₄) alkyl-piperidinyl, —(C₁-C₄)    alkyl-pyrrolidinyl, —(C₁-C₄) alkyl-morpholinyl, wherein the    phthalimidyl, piperidinyl, pyrrolidinyl, or morpholinyl groups are    optionally fused to a phenyl ring and wherein said phthalimidyl,    piperidinyl, pyrrolidinyl, or morpholinyl groups are, the phenyl    portion, or both are optionally substituted with a total of 1, 2, 3,    or 4 groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄    alkoxy, —SO₂—(C₁-C₄) alkyl (C₁-C₄)haloalkyl, or (C₁-C₄)haloalkoxy;    wherein b is 0, 1, or 2.

A Preferred class of compounds of formula IV-a include compounds offormula IV-b, wherein

-   L₃ is a bond, —O—(C₁-C₄)alkyl, or —(C₁-C₄) alkyl-;-   Q is indolyl, -phenyl-C(O)-phenyl, -benzofuranyl-(C₁-C₄)    alkyl-phenyl, indolizinyl, benzofuranyl,    -indolyl-(C₁-C₄)alkyl-phenyl, dibenzo[b,d]furan, or dibenzothienyl,    each of which is optionally substituted with 1, 2, 3, or 4 groups    that are independently C₁-C₆ alkyl, C₁-C₄ alkoxycarbonyl, C₁-C₆    alkoxy, halogen, haloalkyl, haloalkoxy, NR₆R₇, or phenyl; wherein    -   R₆ and R₇ are independently H, C₁-C₆ alkyl, phenyl(C₁-C₆)alkyl,        alkanoyl, phenyl(C₁-C₄)alkanoyl, alkoxycarbonyl,        pyridylcarbonyl, pyrrolidinylcarbonyl, or —SO₂-phenyl, wherein        the cyclic groups are optionally substituted with 1, 2, 3, or 4        groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄        alkoxy, NO₂, OH, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl,        CF₃ or OCF₃.

A Preferred class of compounds of formula IV-b include compounds offormula IV-c, wherein

-   R₂ is —(C₁-C₄) alkyl-phthalimidyl, —(C₁-C₄) alkyl-piperidinyl,    —(C₁-C₄) alkyl-pyrrolidinyl, —(C₁-C₄) alkyl-morpholinyl, wherein the    phthalimidyl, piperidinyl, pyrrolidinyl, or morpholinyl groups are    optionally fused to a phenyl ring and wherein said phthalimidyl,    piperidinyl, pyrrolidinyl, or morpholinyl groups are, the phenyl    portion, or both are optionally substituted with a total of 1, 2, 3,    or 4 groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄    alkoxy, —SO₂—(C₁-C₄) alkyl (C₁-C₄)haloalkyl, or (C₁-C₄)haloalkoxy.

A Preferred class of compounds of formula IV-c include compounds offormula IV-d, wherein

-   R₂ is —(C₁-C₄) alkyl-phthalimidyl, —(C₁-C₄) alkyl-piperidinyl, or    —(C₁-C₄) alkyl-pyrrolidinyl, wherein the phthalimidyl, piperidinyl,    pyrrolidinyl, or morpholinyl groups are optionally fused to a phenyl    ring and wherein said phthalimidyl, piperidinyl, or pyrrolidinyl,    groups are, the phenyl portion, or both are optionally substituted    with a total of 1, 2, 3, or 4 groups that are independently halogen,    C₁-C₄ alkyl, C₁-C₄ alkoxy, —SO₂—(C₁-C₄) alkyl, CF₃, or OCF₃.

A Preferred class of compounds of formula IV-d include compounds offormula IV-e, wherein

-   R₂ is —(C₁-C₄) alkyl-phthalimidyl, optionally fused to a phenyl ring    and wherein said phthalimidyl, or phenyl groups are optionally    substituted with a total of 1, 2, 3, or 4 groups that are    independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, —SO₂—(C₁-C₄)    alkyl, CF₃, or OCF₃.

A Preferred class of compounds of formula IV-c include compounds offormula IV-f, wherein

-   R₂ is phenyl, phenyl(C₁-C₄)alkyl, or (C₁-C₆)alkyl, wherein each    phenyl group is optionally substituted with 1, 2, 3, or 4 groups    that are independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, or    —SO₂—(C₁-C₄) alkyl, CF₃ or OCF₃.

A Preferred class of compounds of formula IV-f include compounds offormula IV-g, wherein

-   R₂ is phenyl or benzyl, wherein each is optionally substituted with    1, 2, 3, or 4 groups that are independently halogen, C₁-C₄ alkyl,    C₁-C₄ alkoxy, —SO₂—(C₁-C₄) alkyl, CF₃ or OCF₃.

A Preferred class of compounds of formula IV-g include compounds offormula IV-h, wherein

-   R₂ is phenyl or benzyl, each of which is substituted at position    number 3 or 4 of the R₂ phenyl ring with a halogen, CF₃ or OCF₃.

A Preferred class of compounds of formula IV-h include compounds offormula IV-i, wherein

-   R₂ is phenyl which is substituted at position number 3 or 4 of the    R₂ phenyl ring with a halogen, CF₃ or OCF₃.

A Preferred class of compounds of formula IV-h include compounds offormula IV-j, wherein

-   R₂ is benzyl, which is substituted at position number 3 or 4 of the    R₂ phenyl ring with a halogen, CF₃ or OCF₃.

A Preferred class of compounds of formula IV-c include compounds offormula IV-k, wherein

-   L₃ is a bond, —O—(C₁-C₄)alkyl, or —(C₁-C₄) alkyl-;-   Q is indolyl, -benzofuranyl-(C₁-C₄) alkyl-phenyl, indolizinyl,    benzofuranyl, -indolyl-(C₁-C₄)alkyl-phenyl, or dibenzo[b,d]furan,    each of which is optionally substituted with 1, 2, 3, or 4 groups    that are independently C₁-C₆ alkyl, C₁-C₄ alkoxycarbonyl, C₁-C₆    alkoxy, halogen, CF₃ or OCF₃.

A Preferred class of compounds of formula IV-k include compounds offormula IV-1, wherein

-   Q is -benzofuranyl-(C₁-C₄) alkyl-phenyl, benzofuranyl, or    dibenzo[b,d]furan, each of which is optionally substituted with 1,    2, 3, or 4 groups that are independently C₁-C₆ alkyl, C₁-C₄    alkoxycarbonyl, C₁-C₆ alkoxy, halogen, CF₃ or OCF₃.

In another aspect, the invention provides a pharmaceutical compositioncomprising a compounds of according to formula I at least onepharmaceutically acceptable solvent, carrier, excipient or adjuvant.

In another aspect, the invention provides a method of treating diabetesin a patient needing such treatment comprising administering a compoundof formula I or a pharmaceutical composition of comprising a compound offormula I.

In another aspect, the invention provides compounds and pharmaceuticallyacceptable salts thereof of formula V, i.e., compounds of formula I,wherein

-   n is 0, 1, or 2;-   R₁ is H, C₁-C₆ alkyl, phenyl(C₁-C₆)alkyl;-   R₂ is C₁-C₆ alkyl, —(C₁-C₄) alkyl-C(O)NH₂, (C₁-C₄) hydroxyalkyl,    phenyl, or phenyl(C₁-C₄) alkyl, wherein each phenyl is optionally    substituted with 1 or 2 groups that are independently halogen, C₁-C₄    alkyl, C₁-C₄ alkoxy, —SO₂—(C₁-C₄) alkyl, haloalkyl, or haloalkoxy;-   R₂₀, R₂₁, R₂₂, and R₂₃ are independently selected from H,    arylalkoxy, arylalkyl, halogen, alkyl, OH, alkoxy, NO₂, NH₂,    NH(C₁-C₆)alkyl, N(C₁-C₆alkyl) (C₁-C₆alkyl), NH-aryl, NHC(O)—(C₁-C₄)    alkyl-aryl, N(C₁-C₄ alkyl)C(O)—(C₁-C₄)alkyl-aryl, N(C₁-C₄)    alkyl-aryl, —NHSO₂-aryl, or —N(C₁-C₄alkyl)SO₂aryl, wherein the aryl    group is optionally substituted with 1, 2, 3, or 4 groups that are    independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, OH, NO₂,    haloalkyl, or haloalkoxy;-   L is —SO₂N(C₁-C₄)alkyl-, —SO₂NH—, —C(O)N(C₁-C₄)alkyl-, —C(O)—(C₁-C₄)    alkyl-, —O—, —NH—, or —N(C₁-C₄ alkyl)-, wherein each alkyl group is    optionally substituted with phenyl, which is optionally substituted    with 1, 2, 3, or 4 groups that are independently C₁-C₆ alkyl, C₁-C₆    alkoxy, halogen, OH, NO₂, haloalkyl, or haloalkoxy;-   L₃ is a bond, —(C₁-C₄)alkyl-O—, —O—(C₁-C₄)alkyl, or —(C₁-C₄)alkyl-;-   the A-ring is-   (a) phenyl substituted with benzofuranyl or dibenzofuranyl, where    -   the phenyl is optionally substituted with 1, 2, or 3 groups that        are independently, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄        haloalkyl, C₁-C₄ haloalkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl, or        N(C₁-C₆)alkyl(C₁-C₆)alkyl, and    -   the dibenzofuranyl and benzofuranyl groups are optionally        substituted with 1, 2, or 3 groups that are independently C₁-C₆        alkyl, C₁-C₄ alkoxycarbonyl, C₁-C₆ alkoxy, halogen, haloalkyl,        haloalkoxy, or NR₆R₇; where        -   R₆ and R₇ are independently H, C₁-C₆ alkyl, C₂-C₆ alkanoyl,            C₁-C₆ alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl, or            —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl; or-   (b) benzofuranyl or dibenzofuranyl, each of which is optionally    substituted with 1, 2, or 3 groups that are independently C₁-C₆    alkyl, C₁-C₄ alkoxycarbonyl, C₁-C₆ alkoxy, halogen, haloalkyl,    haloalkoxy, NO₂, or NR₆R₇.

In still another aspect, the invention provides compounds of formulaV-1, i.e., compounds of formula V wherein R₁ is H.

In still another aspect, the invention provides compounds of formulaV-2, i.e., compounds of formula V-1 wherein

-   n is 0 or 1.-   R₂₂ and R₂₃ are both hydrogen; and-   R₂₀ and R₂₁ are independently selected from H, halogen, C₁-C₄ alkyl,    OH, alkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl, or N(C₁-C₆alkyl) (C₁-C₆alkyl).

In yet another aspect, the invention provides compounds of formula V-3,i.e., compounds of formula V-2 wherein R₂ is phenyl(C₁-C₃)alkyloptionally substituted with 1 or 2 groups that are independentlyhalogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, —SO₂—(C₁-C₄) alkyl, CF₃ or OCF₃. Inanother aspect, R₂ is benzyl or phenethyl optionally substituted asabove. In still another aspect, R₂ is benzyl optionally substituted asabove. In yet another aspect, R2 is phenethyl optionally substituted asabove. In still another aspect the R₂ group is unsubstituted ormonosubstituted.

In yet another aspect, the invention provides compounds of formula V-4,i.e., compounds of formula V-3 wherein R₂ is unsubstituted or monosubstituted benzyl.

In another aspect, preferred compounds of formula V include thecompounds of formula VI,

wherein

-   R₁ is H or C₁-C₂ alkyl;-   R₂ is phenyl, phenyl(C₁-C₄) alkyl (such as benzyl, phenethyl, or    —(CH₂)₄-phenyl)), wherein each phenyl group is optionally    substituted with 1, 2, or 3 groups that are independently halogen,    hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, (C₁-C₄)haloalkyl, or    (C₁-C₄)haloalkoxy;-   v is 0, 1, or 2;-   each R₁₀ is independently hydroxy, halogen, C₁-C₄ alkyl, C₁-C₄    alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, NO₂, NH₂, NH(C₃-C₆)alkyl,    or N(C₁-C₆)alkyl(C₁-C₆)alkyl; and-   L₃ is a bond, —O—(C₁-C₂)alkyl, or —(C₁-C₂)alkyl-;-   Q is benzofuranyl or dibenzofuranyl, each of which is optionally    substituted with 1, 2 or 3 groups that are independently C₁-C₆    alkyl, C₁-C₆ alkoxy, halogen, C₁-C₃ haloalkyl, C₁-C₃ haloalkoxy,    NO₂, or NR₆R₇; where R₆ and R₇ are independently H or C₁-C₆ alkyl.

In one aspect, the invention provides compounds of formula VI-1, i.e.,compounds of formula VI wherein

-   R₂ is phenyl, benzyl, or phenethyl, where the phenyl portion of each    is optionally substituted with 1 or 2 groups that are independently    halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃ or OCF₃; and-   R₂₀, R₂₁, R₂₂, and R₂₃ are independently selected from H, halogen,    alkyl, OH, alkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl, or N(C₁-C₆alkyl)    (C₁-C₆alkyl).

In another aspect, the invention provides compounds of formula VI-2,i.e., compounds of formula VI-1 wherein R₂₂ and R₂₃ are both hydrogen.

In yet another aspect, the invention provides compounds of formula VI-3,i.e., compounds of formula VI-2 wherein

-   R₁ and R₆ are hydrogen; and v is 0 or 1.

In still another aspect, the invention provides compounds of formulaVI-4, i.e., compounds of formula VI-1, VA-2, or VI-3 wherein L₃ is abond.

In yet still another aspect, the invention provides compounds of formulaVII, i.e., compounds of formula VI-4 with the following structure:

In another aspect, the invention provides compounds of formula VII-1,i.e., compounds of formula VII wherein R₁ is H; and R₂₁ is H, NO₂, C₁-C₆alkyl (in another aspect, C₁-C₄ alkyl), or halogen.

In still another aspect, the invention provides compounds of formulaVII-2, i.e., compounds of formula VII-1 wherein L is —C(O)—(C₁-C₄)alkyl-.

In yet another aspect, the invention provides compounds of formulaVII-3, i.e., compounds of formula VII-2 wherein Q is benzofuranyl ordibenzofuranyl, each of which is optionally substituted with 1 or 2groups that are independently C₁-C₄ alkyl, halogen, or C₁-C₃ haloalkyl(in one aspect, CF₃.)

In another aspect, the invention provides compounds of formula VII-4,i.e., compounds according to any one of formulas VII, VII-1, VII-2,VII-3, wherein R₂ is phenyl, benzyl, or phenethyl (more preferably,phenyl or benzyl), where the phenyl portion of each is optionallysubstituted with 1 or 2 groups that are independently halogen, C₁-C₄alkyl (in one aspect methyl or ethyl), C₁-C₄ alkoxy (in one aspect,methoxy or ethoxy), CF₃ or OCF₃. In a different aspect, R₂ isunsubstituted. In still another aspect, R₂ is monosubstituted at the 3or 4 position.

In yet still another aspect, the invention provides compounds of formulaVIII, i.e., compounds of formula VI with the following structure:

where n is 0 or 1.

In another aspect, the invention provides compounds of formula VIII-1,i.e., compounds of formula VIII wherein R₂₁ is H, NO₂, C₁-C₄ alkyl, orhalogen.

In still another aspect, the invention provides compounds of formulaVIII-2, i.e., compounds of formula VIII-1 or formula VIII wherein Q isbenzofuranyl or dibenzofuranyl, each of which is optionally substitutedwith 1 or 2 groups that are independently C₁-C₄ alkyl, halogen, or C₃-C₃haloalkyl (in one aspect, CF₃.)

In yet another aspect, the invention provides compounds of formulaVIII-3, i.e., compounds of formula VIII, VIII-1, or VIII-2, wherein R₂is phenyl, benzyl, or phenethyl (more preferably, phenyl or benzyl),where the phenyl portion of each is optionally substituted with 1 or 2groups that are independently halogen, C₁-C₄ alkyl (in one aspect methylor ethyl), C₁-C₄ alkoxy (in one aspect, methoxy or ethoxy), CF₃ or OCF₃.In a different aspect, R₂ is unsubstituted. In still another aspect, R₂is monosubstituted at the 3 or 4 position.

In yet another aspect, the invention provides compounds of formulaVIII-4, i.e., compounds of formula VIII, VIII-1, VIII-2, or VIII-3,wherein L is —C(O)—(C₁-C₄)alkyl-.

In yet another aspect, the invention provides compounds of formulaVIII-5, i.e., compounds of formula VIII, VIII-1, VIII-2, or VIII-3,wherein L is —O—.

In yet another aspect, the invention provides compounds of formulaVIII-6, i.e., compounds of formula VIII, VIII-1, VIII-2, or VIII-3,wherein L is —NH—, or N(C₁-C₄ alkyl)-.

In yet another aspect, the invention provides compounds of formulaVIII-7, i.e., compounds of formula VIII, VIII-1, VIII-2, or VIII-3,wherein L is —SO₂NH— or —NHSO₂—.

In yet another aspect, the invention provides compounds of formulaVIII-8, i.e., compounds of formula VIII, VIII-1, VIII-2, or VIII-3,wherein L is —SO₂N(C₁-C₄ alkyl)-.

In yet another aspect, the invention provides compounds of formulaVIII-9, i.e., compounds of formula VIII-4, VIII-5, VIII-6, VIII-7, orVIII-8, wherein n is 0.

In yet another aspect, the invention provides compounds of formulaVIII-10, i.e., compounds of formula VIII-4, VIII-5, VIII-6, VIII-7, orVIII-8, wherein n is 1.

In yet another aspect, the invention provides compounds of formulaVIII-11, i.e., compounds of formula VIII-9, wherein R₂ is phenyl.

In yet another aspect, the invention provides compounds of formulaVIII-12, i.e., compounds of formula VIII-10, wherein R₂ is phenyl.

In yet another aspect, the invention provides compounds of formulaVIII-13, i.e., compounds of formula VIII-9, wherein R₂ is benzyl.

In yet another aspect, the invention provides compounds of formulaVIII-14, i.e., compounds of formula VIII-10, wherein R₂ is benzyl.

In another aspect, the invention provides a method of treating diabetes,comprising administering to a patient in need of such treatment apharmaceutically acceptable amount of a compound of formula I, or any ofthe preceding formulas.

In another aspect, the invention encompasses a method of treatingdiabetes comprising administering to a patient in need thereof, apharmaceutically acceptable amount of a compound or salt of formula I ora pharmaceutical composition comprising a compound or salt of formula I,or any of the preceding formulas.

In another aspect, the invention encompasses a method of inhibitingTPT-1B comprising administering to a patient in need thereof, apharmaceutically acceptable amount of a compound or salt of formula I,or any of the preceding formulas or a pharmaceutical compositioncomprising a compound or salt of formula I, or any of the precedingformulas.

In another aspect, the invention encompasses a method of treating canceror neurodegenerative diseases comprising administering to a patient inneed thereof, a pharmaceutically acceptable amount of a compound or saltof formula I, or any of the preceding formulas or a pharmaceuticalcomposition comprising a compound or salt of formula I, or any of thepreceding formulas.

Illustrative compounds of the invention include the following, whichwere named using ChemDraw v. 6.02, which is sold by Cambridgesoft.com inCambridge, Mass., or using Name Pro IUPAC Naming Software, version 5.09,available from Advanced Chemical Development, Inc., 90 Adelaide StreetWest, Toronto, Ontario, M5H 3V9, Canada.

As noted above, the compounds of the invention bind to and preferably,inhibit PTP-1B. As a result that are useful in the treatment of variousdiseases, including controlling or treating Type 2 diabetes, improvingglucose tolerance, and in improving insulin sensitivity in patients inneed thereof. The compounds are also useful in treating or controllingother PTP-1B mediated diseases, such as the treatment of cancer,neurodegenerative diseases and the like.

The term “alkoxy” represents an alkyl group of indicated number ofcarbon atoms attached to the parent molecular moiety through an oxygenbridge. Examples of alkoxy groups include, for example, methoxy, ethoxy,propoxy and isopropoxy.

As used herein, the term “alkyl” includes those alkyl groups of adesigned number of carbon atoms. Alkyl groups may be straight, orbranched. Examples of “alkyl” include methyl, ethyl, propyl, isopropyl,butyl, iso-, sec- and tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl,and the like.

The term “aryl” refers to an aromatic hydrocarbon ring system containingat least one aromatic ring. The aromatic ring may optionally be fused orotherwise attached to other aromatic hydrocarbon rings or non-aromatichydrocarbon rings. Examples of aryl groups include, for example, phenyl,naphthyl, 1,2,3,4-tetrahydronaphthalene and biphenyl. Preferred examplesof aryl groups include phenyl, naphthyl, and anthracenyl. More preferredaryl groups are phenyl and naphthyl. Most preferred is phenyl.

The term “cycloalkyl” refers to a C₃-C₈ cyclic hydrocarbon. Examples ofcycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl.

The terms “halogen” or “halo” indicate fluorine, chlorine, bromine, andiodine.

The term “heterocycloalkyl,” refers to a ring or ring system containingat least one heteroatom selected from nitrogen, oxygen, and sulfur,wherein said heteroatom is in a non-aromatic ring. The heterocycloalkylring is optionally fused to or otherwise attached to otherheterocycloalkyl rings and/or non-aromatic hydrocarbon rings and/orphenyl rings. Preferred heterocycloalkyl groups have from 3 to 7members. Examples of heterocycloalkyl groups include, for example,1,2,3,4-tetrahydroisoquinoline, piperazine, morpholine, piperidine,tetrahydrofuran, pyrrolidine, pyridinonyl, and pyrazole. Preferredheterocycloalkyl groups include piperidinyl, piperazinyl, morpholinyl,pyrrolidinyl, pyridinonyl, dihydropyrrolidinyl, and pyrrolidinonyl.

The term “heteroaryl” refers to an aromatic ring containing at least oneheteroatom selected from nitrogen, oxygen, and sulfur. The heteroarylring may be fused or otherwise attached to one or more heteroaryl rings,aromatic or non-aromatic hydrocarbon rings or heterocycloalkyl rings.Examples of heteroaryl groups include, for example, pyridine, furan,thienyl, 5,6,7,8-tetrahydroisoquinoline and pyrimidine. Preferredexamples of heteroaryl groups include thienyl, benzothienyl, pyridyl,quinolyl, pyrazolyl, pyrimidyl, imidazolyl, benzimidazolyl, furanyl,benzofuranyl, dibenzofuranyl, thiazolyl, benzothiazolyl, isoxazolyl,oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, pyrrolyl,indolyl, pyrazolyl, and benzopyrazolyl.

The compounds of this invention may contain one or more asymmetriccarbon atoms, so that the compounds can exist in differentstereoisomeric forms. These compounds can be, for example, racemates,chiral non-racemic or diastereomers. In these situations, the singleenantiomers, i.e., optically active forms, can be obtained by asymmetricsynthesis or by resolution of the racemates. Resolution of the racematescan be accomplished, for example, by conventional methods such ascrystallization in the presence of a resolving agent; chromatography,using, for example a chiral HPLC column; or derivatizing the racemicmixture with a resolving reagent to generate diastereomers, separatingthe diastereomers via chromatography, and removing the resolving agentto generate the original compound in enantiomerically enriched form. Anyof the above procedures can be repeated to increase the enantiomericpurity of a compound.

When the compounds described herein contain olefinic double bonds orother centers of geometric asymmetry, and unless otherwise specified, itis intended that the compounds include the cis, trans, Z- andE-configurations. Likewise, all tautomeric forms are also intended to beincluded.

The compounds of general Formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes percutaneous, subcutaneous, intravascular (e.g.,intravenous), intramuscular, or intrathecal injection or infusiontechniques and the like. In addition, there is provided a pharmaceuticalformulation comprising a compound of general Formula I and apharmaceutically acceptable carrier. One or more compounds of generalFormula I may be present in association with one or more non-toxicpharmaceutically acceptable carriers and/or diluents and/or adjuvants,and if desired other active ingredients. The pharmaceutical compositionscontaining compounds of general Formula I may be in a form suitable fororal use, for example, as tablets, troches, lozenges, aqueous or oilysuspensions, dispersible powders or granules, emulsion, hard or softcapsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preservative agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients that are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques. In some cases such coatings may be prepared by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatincapsules, wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredient is mixed withwater or an oil medium, for example peanut oil, liquid paraffin or oliveoil.

Formulations for oral use may also be presented as lozenges.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropyl-methylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents and flavoring agents may beadded to provide palatable oral preparations. These compositions may bepreserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents orsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil or amineral oil or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol, glucose or sucrose. Suchformulations may also contain a demulcent, a preservative and flavoringand coloring agents. The pharmaceutical compositions may be in the formof a sterile injectable aqueous or oleaginous suspension. Thissuspension may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents that havebeen mentioned above. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxic parentallyacceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

The compounds of general Formula I may also be administered in the formof suppositories, e.g., for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient that is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials include cocoa butter andpolyethylene glycols.

Compounds of general Formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

For disorders of the eye or other external tissues, e.g., mouth andskin, the formulations are preferably applied as a topical gel, spray,ointment or cream, or as a suppository, containing the activeingredients in a total amount of, for example, 0.075 to 30% w/w,preferably 0.2 to 20% w/w and most preferably 0.4 to 15% w/w. Whenformulated in an ointment, the active ingredients may be employed witheither paraffinic or a water-miscible ointment base.

Alternatively, the active ingredients may be formulated in a cream withan oil-in-water cream base. If desired, the aqueous phase of the creambase may include, for example at least 30% w/w of a polyhydric alcoholsuch as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol,polyethylene glycol and mixtures thereof. The topical formulation maydesirably include a compound which enhances absorption or penetration ofthe active ingredient through the skin or other affected areas. Examplesof such dermal penetration enhancers include dimethylsulfoxide andrelated analogs. The compounds of this invention can also beadministered by a transdermal device. Preferably topical administrationwill be accomplished using a patch either of the reservoir and porousmembrane type or of a solid matrix variety. In either case, the activeagent is delivered continuously from the reservoir or microcapsulesthrough a membrane into the active agent permeable adhesive, which is incontact with the skin or mucosa of the recipient. If the active agent isabsorbed through the skin, a controlled and predetermined flow of theactive agent is administered to the recipient. In the case ofmicrocapsules, the encapsulating agent may also function as themembrane. The transdermal patch may include the compound in a suitablesolvent system with an adhesive system, such as an acrylic emulsion, anda polyester patch. The oily phase of the emulsions of this invention maybe constituted from known ingredients in a known manner. While the phasemay comprise merely an emulsifier, it may comprise a mixture of at leastone emulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make-up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include Tween 60, Span 80, cetostearyl alcohol,myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate,among others. The choice of suitable oils or fats for the formulation isbased on achieving the desired cosmetic properties, since the solubilityof the active compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredients are dissolved or suspended insuitable carrier, especially an aqueous solvent for the activeingredients. The antiinflammatory active ingredients are preferablypresent in such formulations in a concentration of 0.5 to 20%,advantageously 0.5 to 10% and particularly about 1.5% w/w. Fortherapeutic purposes, the active compounds of this combination inventionare ordinarily combined with one or more adjuvants appropriate to theindicated route of administration. If administered per os, the compoundsmay be admixed with lactose, sucrose, starch powder, cellulose esters ofalkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets maycontain a controlled-release formulation as may be provided in adispersion of active compound in hydroxypropylmethyl cellulose.Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules having one or more of the carriers or diluents mentioned foruse in the formulations for oral administration. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, and/or various buffers. Other adjuvants and modes ofadministration are well and widely known in the pharmaceutical art.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient. The daily dose can be administered in one tofour doses per day. In the case of skin conditions, it may be preferableto apply a topical preparation of compounds of this invention to theaffected area two to four times a day.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

For administration to non-human animals, the composition may also beadded to the animal feed or drinking water. It may be convenient toformulate the animal feed and drinking water compositions so that theanimal takes in a therapeutically appropriate quantity of thecomposition along with its diet. It may also be convenient to presentthe composition as a premix for addition to the feed or drinking water.Preferred non-human animals include domesticated animals.

As noted above, the invention also provides methods and compositions forcombination therapy of Type I and Type II diabetes. In one such aspect,the invention provides methods of using compounds of formula I incombination with one or more angiotensin converting enzyme (ACE)inhibitors for improving the cardiovascular risk profile in patientsexperiencing or subject to Syndrome X or type II diabetes(non-insulin-dependent diabetes mellitus), preferably in human type IIdiabetics. These methods may also be characterized as the reduction ofrisk factors for heart disease, stroke or heart attack in a type IIdiabetic.

These methods include the reduction of hyperlipidemia in a patientsexperiencing or subject to Syndrome X or type II diabetes. These methodsinclude methods lowering low density lipoprotein (LDL) blood levels andto increase high density lipoprotein (HDL) blood levels. The methodsherein may further be characterized as useful for inhibiting, preventingor reducing atherosclerosis in a type II diabetics, or for reducing therisk factors thereof.

These methods also include the lowering of free fatty acid blood levelsand triglyceride levels in type II diabetics.

Among the ACE inhibitors which may be utilized with the inventiondescribed herein are quinapril, ramipril, verapamil, captopril,diltiazem, clonidine, hydrochlorthiazide, benazepril, prazosin,fosinopril, lisinopril, atenolol, enalapril, perindropril, perindropriltert-butylamine, trandolapril and moexipril, or a pharmaceuticallyacceptable salt form of one or more of these compounds.

The invention also provides methods of using PTPase inhibitors offormula I for improving the cardiovascular or cerebrovascular riskprofile in patients experiencing or subject to type II diabetes(non-insulin-dependent diabetes mellitus), preferably in human type IIdiabetics or a patient experiencing or subject to Syndrome X. Thesemethods may also be characterized as the reduction of risk factors forheart disease, stroke or heart attack in a type II diabetic or a patientexperiencing or subject to Syndrome X.

The invention also provides methods of using a pharmacologicalcombination of one or more PTPase inhibiting agents, one or morebiguanide agents, and, optionally one or more sulfonlylurea agents fortreatment of type II diabetes or Syndrome X in a patient in need of suchtreatment. Also provided are methods of using these agents to treat orinhibit metabolic disorders mediated by insulin resistance orhyperglycemia in a patient in need thereof. Further included in thisinvention is a method of modulating blood glucose levels in a patient inneed thereof.

Each of these methods comprises administering to a patient in needthereof pharmaceutically effective amounts of:

a) a PTPase inhibiting agent of formula I; andb) a biguanide agent; andc) optionally, a sulfonylurea agent.

Biguanide agents useful with this invention include metformin and itspharmaceutically acceptable salt forms. Sulfonylurea agents useful forthe methods and combinations of this invention may be selected from thegroup of glyburide, glyburide, glipizide, glimepiride, chlorpropamide,tolbutamide, or tolazamide, or a pharmaceutically acceptable salt formof these agents.

This invention also provides pharmaceutical compositions and methods ofusing PTPase inhibitors of formula I in combination with one or morealpha-glucosidase inhibitors, such as miglitol or acarbose, forimproving the cardiovascular risk profile in patients experiencing orsubject to Syndrome X or type II diabetes (non-insulin-dependentdiabetes mellitus), preferably in human type II diabetics. These methodsmay also be characterized as the reduction of risk factors for heartdisease, stroke or heart attack in a patient in such need.

These methods include the reduction of hyperlipidemia in type IIdiabetics, including methods in type II diabetics for lowering lowdensity lipoprotein (LDL) blood levels and to increase high densitylipoprotein (HDL) blood levels. The methods herein may further becharacterized as useful for inhibiting, preventing or reducingatherosclerosis in a type II diabetic or a patient experiencing orsubject to Syndrome X, or the risk factors of either.

These methods also include the lowering free fatty acid blood levels andtriglyceride levels in type II diabetics, or a patient experiencing orsubject to Syndrome X.

Among the alpha-glucosidase inhibitors which may be utilized with theinvention described herein are miglitol or acarbose, or apharmaceutically acceptable salt form of one or more of these compounds.

This invention further provides methods for using a PTPase inhibitor ofthe invention and a sulfonylurea agent for the management of Syndrome Xor type 2 diabetes and for improving the cardiovascular risk profile inpatients experiencing or subject to those maladies. These methods mayalso be characterized as the reduction of risk factors in such patientsfor heart disease, stroke or heart attack in a type II diabetic. Suchmethods include the reduction of hyperlipidemia in a patientsexperiencing or subject to Syndrome X or type II diabetes and includemethods for lowering low density lipoprotein (LDL) blood levels, highdensity lipoprotein (HDL) blood levels, and overall blood lipoproteinlevels. The methods herein may further be characterized as inhibiting,preventing or reducing atherosclerosis in patients subject to orexperiencing Syndrome X or type II diabetes, or the risk factorsthereof. Such methods further include the lowering of free fatty acidblood levels and triglyceride levels in such patients.

Representative sulfonylurea agents include glipizide, glyburide(glibenclamide), chlorpropamide, tolbutamide, tolazamide andglimepriride, or the pharmaceutically acceptable salt forms thereof.

In addition, the invention provides combinations of a PTPase inhibitorof the invention and at least one thiazolidinedione agents. Suchcombinations are useful for treatment, inhibition or maintenance ofSyndrome X or type II diabetes in patients in need of such treatment.Accordingly, methods of using such combinations are provided by theinvention. Thus, the invention provides methods of using these agents totreat or inhibit metabolic disorders mediated by insulin resistance orhyperglycemia in patients in need thereof. Further included in thisinvention are methods of modulating blood glucose levels in a patient inneed thereof.

Each of these methods comprises administering to a patient in needthereof pharmaceutically effective amounts of:

a) a thiazolidinedione agent, such as selected from the group ofpioglitizone and rosiglitazone, or a pharmaceutically acceptable saltform of these agents; and

b) a compound of formula I.

The invention also provides pharmaceutical compositions and methods ofusing PTPase inhibitors in combination with one or more antilipemicagents. Such methods and compositions are useful for improving thecardiovascular risk profile in patients experiencing or subject to typeII diabetes (non-insulin-dependent diabetes mellitus), preferably intype II diabetics or Syndrome X. These methods also include reducing therisk factors for heart disease, stroke or heart attack in a type IIdiabetic or a patient experiencing or subject to Syndrome X. Suchmethods further include the reduction of hyperlipidemia in type IIdiabetics, including such methods in type II diabetics for lowering lowdensity lipoprotein (LDL) blood levels and to increase high densitylipoprotein (HDL) blood levels. These compositions and methods are alsouseful for inhibiting, preventing or reducing atherosclerosis in a typeII diabetic or a patient experiencing or subject to Syndrome X, or therisk factors thereof. In this aspect, the compositions and methods areuseful for lowering of free fatty acid blood levels and triglyceridelevels in type II diabetics, or patients experiencing or subject toSyndrome X.

Representative antilipemic or agents, also known as antihyperlipidemicagents, suitable for use in the invention are bile acid sequestrants,fibric acid derivatives, HMG-CoA reductase inhibitors and nicotinic acidcompounds. Bile acid sequestrant agents useful with this inventioninclude colestipol and colesevelam, and their pharmaceuticallyacceptable salt forms. Fibric acid derivatives which may be used withthe present invention include clifofibrate, gemfibrozil and fenofibrate.HMG-CoA reductase inhibitors, also known as statins, useful with thisinvention include cerivastatin, fluvastatin, atorvastatin, lovastatin,pravastatin and simvastatin, or the pharmaceutically acceptable saltforms thereof. Niacin is an example of a nicotinic acid compound whichmay be used with the methods of this invention. Also useful are lipaseinhibiting agents, such as orlistat.

This invention also provides pharmaceutical compositions that are acombination of a compound of Formula I and an aldose reductase inhibitor(ARI). Such combinations are useful in methods for treating, inhibitingor preventing type II diabetes, or its related and associated symptoms,disorders and maladies. These methods comprise administering to apatient in need of such therapy a pharmaceutically effective amount of acomposition comprising a combination of pharmaceutically effectiveamounts of a compound of formula I and an ARI. These compositions andmethods are useful for the treatment, prevention or inhibition ofdiabetic neuropathy, diabetic nephropathy, retinopathy, keratopathy,diabetic uveitis, cataracts.

Representative suitable ARIs are disclosed in U.S. Pat. Nos. 6,420,426and 6,214,991.

Combinations of the compounds of Formula I and an ARI are also usefulfor inhibition or reduction of risk factors for heart disease, stroke orheart attack in a type II diabetic. Therefore, in this aspect theinvention is useful for reducing hyperlipidemia and/or low densitylipoprotein (LDL) blood levels in type II diabetics. Also included inthis aspect are methods for inhibiting, preventing or reducingatherosclerosis or the risk factors thereof in type II diabetics. Thisaspect includes lowering of free fatty acid blood levels andtriglyceride levels.

This invention also provides methods of using a compound of formula Iand insulin(s) for the management of type I or type II diabetes.Accordingly, the invention provides for combination therapy, i.e., wherea compound of Formula I is administered in combination with insulin.Such combination therapy encompasses simultaneous or sequentialadministration of the compound of Formula I and insulin. The insulinsuseful in this aspect include both naturally occurring and syntheticinsulins.

Insulins useful with the methods and combinations of this inventioninclude rapid acting insulins, intermediate acting insulins, long actinginsulins and combinations of intermediate and rapid acting insulins.

Rapid acting commercially available insulin products include HUMALOG®Brand Lispro Injection (rDNA origin); HUMULIN® Regular Human Injection,USP [rDNA origin]; HUMULIN® Regular U-500 Concentrated Human Injection,USP [rDNA origin]; REGULAR ILETIN® II (insulin injection, USP, purifiedpork) available from Eli Lilly and Co.; and the NOVALIN® Human InsulinInjection and VENOSULIN® BR Buffered Regular Human Injection, eachavailable from Novo Nordisk Pharmaceuticals.

Commercially available intermediate acting insulins useful with thisinvention include, but are not limited to, the HUMULIN® L brand LENTE®human insulin [rDNA origin] zinc suspension, HUMULIN® N NPH humaninsulin [rDNA origin] isophane suspension, LENTE® ILETIN™ II insulinzinc suspension, USP, purified pork, and NPH ILETIN® II isophane insulinsuspension, USP, purified pork, available from Eli Lilly and Company,LANTUS® insulin glargine [rDNA origin] injection, available from AventisPharmaceuticals, and the NOVOLIN L Lente® human insulin zinc suspension(recombinant DNA origin), and NOVOLIN® N NPH human insulin isophanesuspension (recombinant DNA origin) products available from Novo NordiskPharmaceuticals, Inc, Princeton N.J.

Also useful with the methods and formulations of this invention areintermediate and rapid acting insulin combinations, such as the HUMALOG®Mix 75/25 (75% Insulin Lispro Protamine Suspension and 25% InsulinLispro Injection), HUMULIN® 50/50 (50% Human Insulin Isophane Suspensionand 50% Human Insulin Injection) and HUMULIN® 70/30 (70% Human InsulinIsophane Suspension and 30% Human Insulin Injection), each availablefrom Eli Lilly and Company. Also useful are the NOVALIN® 70/30 (70% NPH,Human Insulin Isophane Suspension and 30% Regular, Human InsulinInjection) line of combination products available from Novo NordiskPharmaceuticals.

A commercially available long acting insulin for use with this inventionis the HUMULIN® U Ultralente® human insulin [rDNA origin] extended zincsuspension, available from Eli Lilly and Company.

Also useful in the methods of this invention are inhaled insulinproducts, such as the EXUBERA® inhaled insulin product developed byPfizer Inc. and Aventis SA.

Each of these insulin products can be administered as directed by amedical professional using administrations, dosages and regimens knownin the art, such as those published for each product in the Physicians'Desk Reference, 55 Edition, 2001, published by Medical EconomicsCompany, Inc. at Montvale, N.J., the relevant sections of which areincorporated herein by reference. In this aspect, the inventionincludes, for example, methods for improving the cardiovascular andcerebrovascular risk profiles in patients experiencing or subject totype I or type II diabetes (non-insulin-dependent diabetes mellitus),preferably in human type II diabetics. These methods may also becharacterized as the inhibition or reduction of risk factors for heartdisease, stroke or heart attack in a type II diabetic.

The compounds of the present invention may be prepared by use of knownchemical reactions and procedures. Representative methods forsynthesizing compounds of the invention are presented below. It isunderstood that the nature of the substituents required for the desiredtarget compound often determines the preferred method of synthesis. Allvariable groups of these methods are as described in the genericdescription if they are not specifically defined below.

Methods of Preparation

Compounds with a variety of L linkers (Formula I) can be prepared usingthe chemistry described in general scheme I. Here aryl or heteroarylbromide E-1 is coupled to intermediate E-2 containing a functional groupX that can be modified to provide the desired L-CO₂R substituent. Theinitial coupling reaction between intermediates E-1 and E-2 can often becarried out using a transition metal coupling reaction. Some of the mostuseful reactions of this type include the Suzuki, Stille and Negishireactions. Alternatively, for some examples, it may be more convenientto reverse the coupling functional groups such that metal-M is on theE-1 intermediate and the halogen, preferable Br or I, is on the E-2intermediate. A variety of X substituents may be useful for preparingcompounds with a specific L₁-CO₂R group. Some useful X substituentsinclude sulfonamides, acids, esters, aldehydes, ketones, amides, nitrogroups, anilino groups, hydroxyl groups, sulfides and halides. Someexamples of targets compounds prepared from intermediate E-3 with Xequal to aldehyde or ketone are illustrated in scheme E.

Treatment of carbonyl compound E-4 with a Witting type reagent providesthe unsaturated derivative E-5. If the saturated compound E-6 isrequired, simple hydrogenation with, for example, palladium on carboncan be used. In some cases the carboxylic acid moiety (R═H) may need tobe protected as an ester to facilitate the reactions in the scheme.Carbonyl compound E-4 can also be coupled with an amine derivative usinga reducing agent like sodium triacetoxyborohydride in a reductiveamination reaction to give the corresponding amine E-7. Reduction ofaldehyde or ketone E-4 with sodium borohydride gives the correspondingalcohol. Subsequent conversion of this alcohol to a leaving group suchas a mesylate or halide followed be displacement with a nucleophile suchas a thiol gives sulfide E-8, which if desired can be oxidized to formthe sulfoxide or sulfone. Similarly, the same mesylate or halogenleaving group can be displaced by other nucleophiles like amines oralcohols to give the corresponding amine and ether linkers. The sodiumborohydride reduction product can also be coupled directly to an alkylhalide or substituted phenol using simple alkylation or Mitsunobuconditions respectively.

One method for the preparation of compounds wherein L is —C(O)-alkyl- isdisclosed in Scheme II. In this scheme, the malonate, II-b, is reactedwith the halide, II-a, to form the coupled product, II-c, which is thencoupled to II-d via a transition metal mediated reaction. One of skillin the art will recognized that various bases may be employed to effectthe coupling of II-a to II-b and that the phenyl group in II-b may besubstituted with a variety of groups. Furthermore, the structure of II-dis not limited to dibenzofurans, nor is the function group on II-dlimited to boron derivates; halides, and various sulfonates are alsouseful. Likewise, other coupling reactions, such as the Heck or Stillereactions, are also useful for carrying out the coupling of II-c toII-d. II-e is then hydrolyzed to form the di-acid, which is thendecarboxylated to generate the final product using methods known in theart.

Those having skill in the art will recognize that the starting materialsand reaction conditions may be varied, the sequence of the reactionsaltered, and additional steps employed to produce compounds encompassedby the present invention, as demonstrated by the following examples. Insome cases, protection of certain reactive functionalities may benecessary to achieve some of the above transformations. In general, theneed for such protecting groups as well as the conditions necessary toattach and remove such groups will be apparent to those skilled in theart of organic synthesis.

The disclosures of all articles and references mentioned in thisapplication, including patents, are incorporated herein by reference.

The preparation of the compounds of the present invention is illustratedfurther by the following examples, which are not to be construed aslimiting the invention in scope or spirit to the specific procedures andcompounds described in them.

EXAMPLE 1 Preparation of2-Benzyl-4-[4′-(2-benzyl-benzofuran-3-yl)-biphenyl-4-yl]-4-oxo-butyricacid

Step 1: Preparation of5-[2-(4-Bromophenyl)-2-oxoethyl]-2,2-dimethyl-[1,3]dioxane-4,6-dione

A solution of Meldrum's acid (5.0 g, 35 mmol) in anhyd THF (25 mL) wasadded cautiously to a stirred suspension of sodium hydride (95%, 960 mg,38 mmol) in anhyd THF (25 mL). The resulting solution was stirred atroom temperature for 1 h. A solution of 2,4′-dibromoacetophenone (11.6g, 42 mmol) in anhyd THF (25 mL) was added dropwise, and the resultantsolution was stirred at room temperature for 16-24 h (TLC control). Thereaction mixture was poured into water (50 mL), acidified to pH 2-3 with0.5 N hydrochloric acid and extracted with ethyl acetate (3×50 mL). Thecombined extract was washed with water, sat'd aq NaCl, dried over anhydMgSO₄, filtered and concentrated in vacuo. Trituration and filtrationfrom MeOH afforded the title compound as a white solid (6.56 g).

Step 2: Preparation of2-Benzyl-3-[4-(4,4,5,5-tetramethyl-([1,3,2]-dioxaborolan-2-yl)phenyl]-benzofuran

A solution of bis-(pinacolato)diboron (2.64 g, 10.41 mmol) in anhyd DMSO(20 mL) was added to a stirred suspension of trifluoromethanesulfonicacid-4-(2-benzylbenzofuran-3 yl)phenyl ester, (4.09 g, 9.47 mmol) andpotassium acetate (3.71 g, 37.9 mmol) in anhyd DMSO (20 mL).[1,1′-Bis(diphenylphosphino)-ferrocene]dichloropalladium(II)-DCM complex(770 mg, 0.95 mmol) was added as a solid, and the resulting suspensionwas heated to 80° C. for 4 h. The reaction mixture was cooled to roomtemperature, diluted with diethyl ether (150 mL), washed with water(2×50 mL), sat'd aq NaCl (3×50 mL), dried over anhyd MgSO₄, filtered andconcentrated in vacuo. Purification of the product by flash columnchromatography, using 10% ethyl acetate/hexane as eluent, afforded thetitle compound as a white solid (2.96 g).

Step 3: Preparation of5-{2-[4′-(2-Benzylbenzofuran-3-yl)-biphen-4-yl]-2-oxoethyl}-2,2-dimethyl-[1,3]dioxane-4,6-dione

A solution of2-benzyl-3-[4′-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)phenyl]-benzofuran(500 mg, 1.22 mmol) in anhyd DMSO (5 mL) was added to a stirredsuspension of5-[2-(4-bromophenyl)-2-oxoethyl]-2,2-dimethyl-[1,3]dioxane-4,6-dione(436 mg, 1.22 mmol) and tripotassium phosphate (1.04 g, 4.88 mmol) inanhyd DMSO (5 mL).[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)-DCM complex(100 mg, 0.12 mmol) was added as a solid, and the resulting suspensionwas heated to 80° C. for 2 h. The reaction mixture was cooled to roomtemperature, diluted with diethyl ether (150 mL), washed with water(2×50 mL), sat'd aq NaCl (3×50 mL), dried over anhyd MgSO₄, filtered andconcentrated in vacuo. Purification by flash column chromatography(50-60% ethyl acetate in heptane) afforded the title compound as anoff-white solid (502 mg).

Step 4: Preparation of5-Benzyl-5-{2-[4′-(2-benzylbenzofuran-3-yl)-biphen-4-yl]-2-oxoethyl}-2,2-dimethyl-[1,3]dioxane-4,6-dione

A solution of5-{2-[4′-(2-benzylbenzofuran-3-yl)-biphen-4-yl]-2-oxoethyl}-2,2-dimethyl-[1,3]dioxane-4,6-dione(200 mg, 0.37 mmol) in THF/DMF (5:1; 6 mL) was added dropwise to astirred suspension of sodium hydride (95%, 10.2 mg, 0.40 mmol) in anhydTHF (5 mL) at room temperature. The clear solution was stirred at roomtemperature for 30 min and then a solution of benzyl bromide (76 mg,0.44 mmol) in THF (5 mL) was added dropwise, followed by the addition oftetra-n-butylammonium iodide (5 mg) as a solid. The reaction mixture waswarmed to 60° C. for 4 h (TLC control), cooled to room temperature andthen water (10 mL) was added cautiously. The reaction mixture wasextracted with diethyl ether (3×15 mL). The combined organic extractswere washed successively with water (2×10 mL), sat'd aq NaCl (3×10 mL),dried over anhyd MgSO₄, filtered and concentrated in vacuo. Purificationby trituration and filtration from MeOH afforded the title compound as apale yellow solid (210 mg).

Step 5: Preparation of2-Benzyl-4-[4′-(2-benzylbenzofuran-3-yl)biphen-4-yl]-4-oxobutyric acid

2 N Hydrochloric acid (1 mL) was added to a stirred solution of5-benzyl-5-{2-[4′-(2-benzylbenzofuran-3-yl)-biphen-4-yl]-2-oxoethyl}-2,2-dimethyl-[1,3]dioxane-4,6-dione(200 mg) in THF (5 mL), and the resultant solution was heated at 70° C.for 6 h and then cooled to room temperature and concentrated in vacuo.The resulting solid was redissolved in DMSO (5 mL), and heated to 150°C. for 3 h before being cooled to room temperature, and diluted withwater (20 mL), and extracted with ethyl acetate (3×20 mL). The combinedextract was washed with water (2×10 mL), sat'd aq NaCl (3×10 mL), driedover anhyd MgSO₄, filtered and concentrated in vacuo. Purification bytrituration and filtration from MeOH afforded the title compound as apale yellow solid (65 mg).

EXAMPLE 2 Preparation of4-(4′-Dibenzofuran-4-yl-biphenyl-4-yl)-4-oxo-2-(3-trifluoromethyl-benzyl)-butyricacid

Step 1: Preparation of Diallyl-2-(3-trifluoromethylbenzyl) malonate

Diallyl malonate (1.2 g, 6.52 mmol) was added dropwise to a stirredsuspension of sodium hydride (95%, 172 mg, 6.85 mmol) in anhyd THF (30mL) at room temperature. The clear solution was stirred at roomtemperature for 30 min and then a solution of 3-trifluoromethylbenzylbromide (1.7 g, 7.18 mmol) in THF (10 mL) was added dropwise. Thereaction mixture was warmed to 50° C. for 4 h (TLC control), cooled toroom temperature and then water (10 mL) was added cautiously. Thereaction mixture was acidified to pH 3 with 2 N hydrochloric acid andthen extracted with ethyl acetate (3×30 mL). The combined organicextracts were washed successively with water and sat'd aq NaCl, driedover anhyd MgSO₄, filtered and concentrated in vacuo. Purification byflash column chromatography (10% ethyl acetate in heptane) afforded thetitle compound as a colorless oil (1.03 g).

Step 2: Preparation ofDiallyl-2-[2-(4-bromophenyl)-2-oxoethyl]-2-(3-trifluoromethylbenzyl)malonate

Diallyl-2-(3-trifluoromethylbenzyl)malonate (1.03 g, 3.01 mmol) in anhydTHF (20 mL) was added dropwise to a stirred suspension of sodium hydride(95%, 84 mg, 3.31 mmol) in anhyd THF (20 mL) at room temperature. Theclear solution was stirred at room temperature for 30 min and then asolution of 2,4′-dibromoacetophenone (1.0 g, 3.61 mmol) in THF (10 mL)was added dropwise. The reaction mixture was warmed to 50° C. for 3 h(TLC control), cooled to room temperature and then water (10 mL) wasadded cautiously. The reaction mixture was acidified to pH 3 with 2 Nhydrochloric acid and then extracted with ethyl acetate (3×30 mL). Thecombined extract was washed with water, sat'd aq NaCl, dried over anhydMgSO₄, filtered and concentrated in vacuo. Purification by flash columnchromatography (10% ethyl acetate in heptane) afforded the titlecompound as a colorless oil (1.23 g).

Step 3: Preparation ofMethyl-4-(4-bromophenyl)-4-oxo-2-(3-trifluoromethylbenzyl)butyrate

3 N Sodium hydroxide (3 mL) was added dropwise to a stirred solution ofdiallyl-2-[2-(4-bromophenyl)-2-oxoethyl]-2-(3-trifluoromethylbenzyl)malonatein THF (20 mL) and MeOH (3 mL), and the reaction was stirred at roomtemperature until complete (TLC control). The reaction mixture waswashed with diethyl ether (2×10 mL), then acidified to pH 2 with 6 Nhydrochloric acid and extracted with ethyl acetate (3×20 mL). Thecombined organic extracts were washed with water, sat'd aq NaCl, driedover anhyd MgSO₄, filtered and concentrated in vacuo to yield2-[2-(bromophenyl)-2-oxoethyl]-2-(3-trifluoromethyl-benzyl)malonic acidas a pale yellow solid, which was used immediately without furtherpurification.

The crude malonic acid was redissolved in dioxane (25 mL). 6 NHydrochloric acid (3 drops) was added and then the solution was heatedto reflux for 16 h, and then cooled to room temperature and diluted withethyl acetate (50 mL). The organic phase was washed with water, sat'd aqNaCl, dried over anhyd MgSO₄, filtered and concentrated in vacuo toyield 4-(4-bromophenyl)-4-oxo-2-(3-trifluoromethylbenzyl)butyric acid asa white solid (790 mg), which was used without further purification.

The crude acid, from the previous step, was dissolved in anhyd MeOH (10mL) and cooled to 0° C. Thionyl chloride (340 mg, 220 μL, 2.85 mmol) wasadded dropwise. The reaction mixture was stirred at 0° C. for 30 min andthen warmed to room temperature and stirred for 3 h. The reactionmixture was poured into ice water. A saturated solution of sodiumhydrogen carbonate was added to adjust the pH to 8-9, and then thesolution was extracted with diethyl ether (3×20 mL). The combinedorganic extracts were washed with water, sat'd aq NaCl, dried over anhydMgSO₄, filtered and concentrated in vacuo. Purification by flash columnchromatography (20% ethyl acetate in hexane) afforded the title compoundas a colorless oil (640 mg).

Step 4: Preparation ofMethyl-4-(4′-hydroxybiphen-4-yl)-4-oxo-2-(3-trifluoromethylbenzyl)butyrate

A solution of 4-hydroxyphenylboronic acid (160 mg, 1.2 mmol) in MeOH (3mL) was added to a stirred solution ofmethyl-4-(4-bromophenyl)-4-oxo-2-(3-trifluoromethyl-benzyl)butyrate (270mg, 0.6 mmol) in toluene (10 mL).Tetrakis-(Triphenylphosphine)-palladium(0) (21 mg, 4 mol %) and 2 Nsodium carbonate (0.75 mL, 1.5 mmol) were added and then the reactionwas heated to 90° C. (oil bath temp.) for 4-5 h until complete (TLCcontrol). The reaction mixture was cooled to room temperature, acidifiedto pH 3 with 0.5 N hydrochloric acid and partitioned between water andethyl acetate. The phases were separated, the aqueous phase beingfurther extracted with ethyl acetate (2×20 mL). The combined organicextracts were washed with water and sat'd aq NaCl, dried over anhydMgSO₄, filtered and concentrated. Trituration and filtration from MeOHafforded the title compound has a white solid (200 mg).

Step 5: Preparation ofMethyl-4-oxo-4-(4′-trilfouormethanesulfonyloxy-biphen-4-yl)-2-(3-trifluoromethyl-benzyl)butyrate

To a solution ofMethyl-4-(4′-hydroxybiphen-4-yl)-4-oxo-2-(3-trifluoromethyl-benzyl)butyrate(200 mg, 0.45 mmol) in methylene chloride (6 mL) was added triethylamine(91 mg, 125 μL, 0.9 mmol), and2-[N,N-bis(trifluoromethylsulfonyl)-amino]pyridine (179 mg, 0.48 mmol).The reaction mixture was stirred at room temperature for 2 h (TLCcontrol), diluted with diethyl ether (30 mL), and washed with 1 Nhydrochloric acid, water and sat'd aq NaCl, dried over anhyd MgSO₄,filtered and concentrated. Purification by flash column chromatography(20-30% ethyl acetate in heptane) afforded the title compound has awhite solid (240 mg).

Step 6: Preparation ofMethyl-4-(4′-dibenzofuran-4-ylbiphen-4-yl)-4-oxo-2-(3-trifluoromethyl-benzyl)butyrate

A solution of dibenzofuran-4-boronic acid (133 mg, 0.63 mmol) inmethanol (5 mL) was added to a stirred solution ofmethyl-4-oxo-4-(4′-trilfouormethanesulfonyloxy-biphen-4-yl)-2-(3-trifluoromethyl-benzyl)butyrate(240 mg, 0.42 mmol) and tetrakis(triphenylphosphine)-palladium(0) (25mg, 5 mol %) in toluene (20 mL). 2 N sodium carbonate (0.5 mL, 1.0 mmol)was added and then the reaction was heated to 90° C. (oil bath temp.)for 2-3 h until complete (TLC control).

The reaction mixture was cooled to room temperature and partitionedbetween water and ethyl acetate. The phases were separated, the aqueousphase being further extracted with ethyl acetate (2×20 mL). The combinedextract was washed with water and sat'd aq NaCl. The organic solutionwas dried over anhyd MgSO₄, filtered and concentrated in vacuo.Purification by flash column chromatography (20-30% ethyl acetate inheptane) afforded the title compound has a white solid (230 mg).

Step 7: Preparation of4-(4′-Dibenzofuran-4-ylbiphen-4-yl)-4-oxo-2-(3-trifluoromethybenzyl)butyricacid

2 N Sodium hydroxide solution (1 mL) was added dropwise to a stirredsolution ofmethyl-4-(4′-dibenzofuran-4-ylbiphen-4-yl)-4-oxo-2-(3-trifluoromethyl-benzyl)butyrate(220 mg) in tetrahydrofuran (5 mL) and methanol (2 mL). The clearreaction mixture was stirred at room temperature until the reaction wascomplete (TLC control), and then diluted with water (5 mL), andacidified to pH 3 with 2N hydrochloric acid. The reaction mixture wasextracted with ethyl acetate (2×20 mL). The combined organic extractswere washed with water, sat'd aq NaCl, dried over anhyd MgSO₄, filteredand concentrated in vacuo. Purification by flash column chromatography(5-10% methanol in methylene chloride) afforded the title compound has awhite solid (190 mg). Rf: 0.60 (10% methanol in dichloromethane); 1H-NMR(CDCl₃, 300 MHz): δ 8.06 (4H, m, Ar—H), 7.96 (2H, m, Ar—H), 7.77 (4H, t,J=9 Hz, Ar—H), 7.62 (2H, t, J=9 Hz, Ar—H), 7.47 (6H, m, Ar—H), 7.37 (1H,t, J=8 Hz, Ar—H), 3.46 (2H, m), 3.26 (1H, dd, J=16, 7 Hz), 3.12 (1H, m),3.02 (1H, dd, J=16, 8 Hz); ESI-LCMS e/z calcd for C₃₆H₂₅F₃O₄: 578.583,found 579 (M+H)⁺, 601 (M+Na)⁺.

EXAMPLE 3

The following compounds were prepared essentially according to themethods and procedures described above in the schemes and examples 1 and2.

In another aspect, the invention provides a compound according toformula I selected from the group consisting of

-   ({4′-[3-(benzylamino)imidazo[1,2-a]pyridin-2-yl]biphenyl-4-yl}oxy)(phenyl)acetic    acid;-   {[4′-(5-methyl-1H-indol-1-yl)biphenyl-4-yl]oxy}(phenyl)acetic acid;-   ({4′-[3-(butylamino)imidazo[1,2-a]pyridin-2-yl]biphenyl-4-yl}oxy)(phenyl)acetic    acid;-   methyl    ({4′-[(2-benzoylphenoxy)methyl]biphenyl-4-yl}oxy)(phenyl)acetate;-   methyl    ({4′-[(2-benzylphenoxy)methyl]biphenyl-4-yl}oxy)(phenyl)acetate;-   methyl    ({4′-[(9H-fluoren-2-yloxy)methyl]biphenyl-4-yl}oxy)(phenyl)acetate;-   methyl    ({4′-[(3-benzoylphenoxy)methyl]biphenyl-4-yl}oxy)(phenyl)acetate;-   ({4′-[(3-benzoylphenoxy)methyl]biphenyl-4-yl}oxy)(phenyl)acetic    acid;-   ({4′-[(2-benzoylphenoxy)methyl]biphenyl-4-yl}oxy)(phenyl)acetic    acid;-   2-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]oxy}-3-phenylpropanoic    acid;-   {[4′-(1-butylindolizin-2-yl)biphenyl-4-yl]oxy}(phenyl)acetic acid;-   [4-(1-benzyl-1H-indol-6-yl)phenoxy](phenyl)acetic acid;-   ({4′-[10-(ethoxycarbonyl)pyrido[1,2-a]indol-3-yl]biphenyl-4-yl}oxy)(phenyl)acetic    acid;-   {[4′-(1-benzofuran-2-yl)biphenyl-4-yl]oxy}(phenyl)acetic acid;-   {[4′-(1H-indol-1-yl)biphenyl-4-yl]oxy}(phenyl)acetic acid;-   methyl    {[4′-(1-benzyl-1H-indol-6-yl)biphenyl-4-yl]oxy}(phenyl)acetate;-   4-(4′-Dibenzofuran-4-yl-biphenyl-4-yl)-4-oxo-2-(3-trifluoromethyl-benzyl)-butyric    acid;-   {[4′-(1-benzyl-1H-indol-6-yl)biphenyl-4-yl]oxy}(phenyl)acetic acid;-   {[4′-(1-benzyl-1H-indol-5-yl)biphenyl-4-yl]oxy}(phenyl)acetic acid;-   2-{[4′-(1-butylindolizin-2-yl)biphenyl-4-yl]oxy}propanoic acid;-   N-{[4′-(1-butylindolizin-2-yl)biphenyl-4-yl]sulfonyl}phenylalanine;-   N-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]sulfonyl}phenylalanine;-   N-benzyl-N-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]sulfonyl}glycine;-   ({[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]sulfonyl}amino)(phenyl)acetic    acid;-   (2R)-2-{[4′-(1-butylindolizin-2-yl)biphenyl-4-yl]oxy}-3-phenylpropanoic    acid;-   4-(4-Dibenzofuran-4-yl-phenyl)-4-oxo-2-(3-trifluoromethyl-benzyl)-butyric    acid;-   (2S)-2-{[4′-(1-butylindolizin-2-yl)biphenyl-4-yl]oxy}-4-phenylbutanoic    acid;-   ({4′-[(2-butyl-1-benzofuran-3-yl)methyl]biphenyl-4-yl}oxy)(phenyl)acetic    acid;-   ethyl    N-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]sulfonyl}-N-methylphenylalaninate;-   N-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]sulfonyl}-N-methylphenylalanine;-   ethyl    N-{[4′-(1-butylindolizin-2-yl)biphenyl-4-yl]carbonyl}phenylalaninate;-   N-{[4′-(1-butylindolizin-2-yl)biphenyl-4-yl]carbonyl}phenylalanine;-   {[2″-(1,3-benzoxazol-2-yl)-1,1′:4′,1″-terphenyl-4-yl]oxy}(phenyl)acetic    acid;-   ({4′-[(2-butyl-1-benzofuran-3-yl)carbonyl]biphenyl-4-yl}oxy)(phenyl)acetic    acid;-   methyl    {[4′-(1-butylindolizin-2-yl)biphenyl-4-yl]sulfonyl}(phenyl)acetate;-   N-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]carbonyl}phenylalanine;-   N-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]carbonyl}-N-methylphenylalanine;-   {[4′-(1-butylindolizin-2-yl)biphenyl-4-yl]sulfonyl}(phenyl)acetic    acid;-   ({[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]carbonyl}amino)(phenyl)acetic    acid;-   2-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]oxy}propanoic acid;-   {[4′-(1-butylindolizin-2-yl)biphenyl-4-yl]amino}(phenyl)acetic acid;-   N-({4′-[(2-butyl-1-benzofuran-3-yl)methyl]biphenyl-4-yl}sulfonyl)-N-methylphenylalanine;-   N-({4′-[(2-butyl-1-benzofuran-3-yl)methyl]biphenyl-4-yl}carbonyl)-N-methylphenylalanine;-   N-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]carbonyl}-N-methylvaline;-   2-benzyl-4-[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]-4-oxobutanoic    acid;-   N-[4′-(2-benzyl-1-benzofuran-3-yl)-3-nitrobiphenyl-4-yl]phenylalanine;-   N-[4′-(2-benzyl-1-benzofuran-3-yl)-3-nitrobiphenyl-4-yl]-N-methyl-L-phenylalanine;-   N-[4′-(2-benzyl-1-benzofuran-3-yl)-3-nitrobiphenyl-4-yl]-N-methyl-D-phenylalanine;-   N-{[4′-(2-benzyl-1-benzofuran-3-yl)-3-fluorobiphenyl-4-yl]sulfonyl}phenylalanine;-   {[4′-(1-benzothien-2-yl)biphenyl-4-yl]oxy}(phenyl)acetic acid;-   N-[4′-(2-benzyl-1-benzofuran-3-yl)-3-nitrobiphenyl-4-yl]-N-(4-nitrobenzoyl)-L-phenylalanine;-   [(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)oxy](phenyl)acetic acid;-   N-{[4′-(2-benzyl-1-benzofuran-3-yl)-3-fluorobiphenyl-4-yl]sulfonyl}-N-methylphenylalanine;-   [(4″-butyl-1,1′:4′,1″-terphenyl-4-yl)oxy](phenyl)acetic acid;-   N²-[4′-(2-benzyl-1-benzofuran-3-yl)-3-nitrobiphenyl-4-yl]glutamine;-   4-[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-4-oxobutanoic    acid;-   ({4′-[(2-benzyl-7-fluoro-1-benzofuran-3-yl)carbonyl]biphenyl-4-yl}oxy)(phenyl)acetic    acid;-   N-[4′-(2-benzyl-1-benzofuran-3-yl)-3-nitrobiphenyl-4-yl]methionine;-   N-[4′-(2-benzyl-1-benzofuran-3-yl)-3-nitrobiphenyl-4-yl]serine;-   N-[4′-(2-benzyl-1-benzofuran-3-yl)-3-nitrobiphenyl-4-yl]alanine;-   N-{4′-[(2-benzyl-7-ethoxy-1-benzofuran-4-yl)methyl]-3-nitrobiphenyl-4-yl}phenylalanine;-   N-[4′-(2-benzyl-4-fluoro-1-benzofuran-3-yl)-3-nitrobiphenyl-4-yl]phenylalanine;-   2-benzyl-4-[4′-(2-benzyl-1-benzofuran-3-yl)-3,5-dimethylbiphenyl-4-yl]-4-oxobutanoic    acid;-   2-benzyl-4-[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-3-yl]-4-oxobutanoic    acid;-   2-benzyl-4-[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-2-yl]-4-oxobutanoic    acid;-   N-{4′-(2-benzyl-1-benzofuran-3-yl)-3-[(phenylacetyl)amino]biphenyl-4-yl}phenylalanine;-   4-[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]-2-[4-(methylsulfonyl)benzyl]-4-oxobutanoic    acid;-   N-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]sulfonyl}-4-fluorophenylalanine;-   N-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]sulfonyl}-4-fluoro-N-methylphenylalanine;-   N-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]sulfonyl}-3-fluorophenylalanine;-   N-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]sulfonyl}-3-fluoro-N-methylphenylalanine;-   N-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]sulfonyl}-N-ethyl-4-fluorophenylalanine;-   N-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]sulfonyl}leucine;-   N-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]sulfonyl}alanine;-   2-({[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]sulfonyl}amino)butanoic    acid;-   N-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]sulfonyl}-N-[3-(trifluoromethyl)benzyl]leucine;-   2-{([4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]sulfonyl)[3-(trifluoromethyl)benzyl]amino}butanoic    acid;-   methyl    4-(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)-4-oxo-2-[3-(trifluoromethyl)benzyl]butanoate;-   [(4′-{[(9-oxo-9H-fluoren-1-yl)oxy]methyl}biphenyl-4-yl)oxy](phenyl)acetic    acid;-   methyl {[4′-(1-benzofuran-2-yl)biphenyl-4-yl]oxy}(phenyl)acetate;-   ({4′-[3-(butylamino)imidazo[1,2-a]pyridin-2-yl]biphenyl-4-yl}amino)(phenyl)acetic    acid;-   {[4′-(1-benzothien-3-yl)biphenyl-4-yl]oxy}(phenyl)acetic acid;-   methyl    {[4′-(1-benzyl-1H-indol-5-yl)biphenyl-4-yl]oxy}(phenyl)acetate;-   ethyl    ({[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]sulfonyl}amino)(phenyl)acetate;-   methyl 2-(4-benzo[b]naphtho[2,3-d]furan-11-ylphenoxy)propanoate;-   3-({[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]carbonyl}amino)butanoic    acid;-   N-{[4′-(5-methyl-1H-indol-1-yl)biphenyl-4-yl]carbonyl}phenylalanine;-   N-{[4′-(1H-indol-1-yl)biphenyl-4-yl]carbonyl}-L-phenylalanine;-   N-(3′-fluoro-3-nitro-1,1′:4′,1″-terphenyl-4-yl)phenylalanine;-   2-benzyl-4-[4′-(1H-indol-1-yl)biphenyl-4-yl]-4-oxobutanoic acid;-   2-[4′-(2-Benzyl-benzofuran-3-yl)-3-nitro-biphenyl-4-ylamino]-3-phenyl-propionic    acid;-   4-(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)-4-oxo-2-[3-(trifluoromethyl)benzyl]butanoic    acid;-   [(4′-dibenzo[b,d]thien-4-ylbiphenyl-4-yl)oxy](phenyl)acetic acid;-   (4′-Dibenzofuran-4-yl-biphenyl-4-ylmethoxyimino)-phenyl-acetic acid;-   3-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethoxyimino)-3-phenyl-propionic    acid;-   [4′-(5-Chloro-indol-1-yl)-biphenyl-4-yloxy]-phenyl-acetic acid;-   (3-Chloro-4′-dibenzofuran-4-yl-biphenyl-4-yloxy)-phenyl-acetic acid;-   (4′-Dibenzofuran-4-yl-2-methyl-biphenyl-4-yloxy)-phenyl-acetic acid;-   (4′-Dibenzofuran-4-yl-3-fluoro-biphenyl-4-yloxy)-phenyl-acetic acid;-   (2-Chloro-4′-dibenzofuran-4-yl-biphenyl-4-yloxy)-phenyl-acetic acid;    and-   (4′-Dibenzofuran-4-yl-2-trifluoromethyl-biphenyl-4-yloxy)-phenyl-acetic    acid.

In still another aspect, the invention provides compounds of formula Iselected from

2-[4′-(2-Benzyl- Isolated as an off-white solid. R_(f) 0.32benzofuran-3-yl)-3- (10% Methanol-90% Methylene Chloride); ¹Hfluoro-biphenyl-4- NMR (CDCl₃) 12.8 (br. s, 1H), 8.57 (br. s,sulfonylamino]-3-phenyl- 1H), 7.93-7.16 (m, 21 H), 4.29 (s, 2H),propionic acid; 3.97 (m, 1H); 3.02-2.75 (m, 2H); LCMS m/z calcd forC₃₆H₂₈FNO₅S: 605.68 found 604.0 (M + 1). 2-{[4′-(2-Benzyl- Isolated asan off white solid. R_(f) 0.36 benzofuran-3-yl)-3- (10% Methanol-90%Methylene Chloride); ¹H fluoro-biphenyl-4- NMR (CDCl₃) 7.79 (tr, J = 7.8Hz, 1H), 7.69- sulfonyl]-methyl-amino}- 7.61 (m, 4H), 7.49 (d, J = 7.2Hz, 1H), 7.42 3-phenyl-propionic acid; (d, J = 8.4 Hz, 1H), 7.32-7.12(14H), 4.94 (q, J = 5.1 Hz, 1H), 4.26 (s, 2H), 3.32 (dd, J = 14.4, 5.7Hz, 1H), 3.07 (3H), 3.07-2.92 (1H). 4-[4′-(2-Benzyl- Isolated as a beigefoam. R_(f) 0.39 (10% benzofuran-3-yl)- Methanol-90% MethyleneChloride); ¹H NMR biphenyl-4-yl]-2-[2-(1,3- (CDCl₃) 8.05 (d, J = 8.1 Hz,2H), 7.82-7.23 dioxo-1,3-dihydro- (m, 19H), 4.24 (s, 2H), 3.86 (br s,2H), isoindol-2-yl)-ethyl]-4- 3.60 (dd, J = 18.0, 7.6 Hz, 1H), 3.29-3.13oxo-butyric acid; (m, 2H), 2.20 (m, 1H), 2.01 (m, 1H); LCMS m/z calcdfor C₄₁H₃₁NO₆: 633.69 found 634.0 (M + 1). 2-Benzyl-4-[4′-(2- Lightyellow solid. R_(f) 0.43 (10% benzyl-benzofuran-3-yl)- Methanol-90%Methylene Chloride ); ¹H NMR 3,5-dimethyl-biphenyl-4- (DMSO-d6) 7.79 (d,J = 8.1 Hz, 2H), 7.62- yl]-4-oxo-butyric acid; 7.16 (m, 18H), 4.26 (s,2H), 3.11-2.76 (m, 5H), 2.13 (s, 6H); LCMS m/z calcd for C₄₀H₃₄O_(4:)578.7 found 579.0 (M + 1). 2-Benzyl-4-(4′-indol- Isolated as a whitesolid. R_(f) 0.44 1-yl-biphenyl-4-yl)-4- (10% Methanol-90% MethyleneChloride); ¹H oxo-butyric acid; NMR (DMSO-d6) 12.2 (br. s, 1H),8.03-7.62 (m, 11H), 7.29-7.13 (m, 7H), 6.72 (br s, 1H), 3.46-3.37 (m,1H), 3.16-2.81 (m, 4H); LCMS m/z calcd for C₃₁H₂₅NO_(3:) 459.5 found460.3 (M + 1). 2-Benzyl-4-[4′-(2- Isolated as a light yellow foam. R_(f)benzyl-benzofuran-3-yl)- 0.33 (10% Methanol-90% Methylene Chloride);biphenyl-3-yl]-4-oxo- ¹H NMR (DMSO-d6) 8.21 (s, 8.21, 1H), butyric acid;8.00-7.87 (m, 4H), 7.68-7.56 (m, 5H), 7.35-7.15 (m, 12H), 4.28 (s, 2H),3.53- 3.44 (m, 1H), 3.18-2.80 (m, 4H); LCMS m/z calcd for C₃₈H₃₀O_(4:)550.6 found 551.3 (M + 1). 2-Benzyl-4-[4′-(2- Isolated as a yellow foam.R_(f) 0.35 (10% benzyl-benzofuran-3-yl)- Methanol-90% MethyleneChloride); ¹H NMR biphenyl-2-yl]-4-oxo- (CDCl₃) 6.94-7.69 (m, 22H), 4.25(s, 2H), butyric acid; 3.12-3.05 (m, 1H), 2.90-2.74 (m, 2H), 2.56 (dd,J₁ = 13.5 Hz, J₂ = 8.2 Hz, 1H), 2.49 (dd, , J₁ = 18.0 Hz, J₂ = 4.6 Hz,1H); LCMS m/z calcd for C₃₈H₃₀O_(4:) 550.6 found 551.3 (M + 1).4-[4′-(2-Benzyl- Isolated as a dark yellow solid., R_(f)benzofuran-3-yl)- 0.41′ (10% Methanol-90% Methylene Chloride);biphenyl-4-yl]-2-(4- ¹H NMR (CDCl₃) 8.02 (d, J = 8.4 Hz, 2H),methanesulfonyl-benzyl)- 7.89 (d, J = 8.1 Hz, 2H), 7.74 (d, J = 10.54-oxo-butyric acid; Hz, 4H), 7.63 (d, J = 7.5 Hz, 3H), 7.48 (d, J = 5.1Hz, 3H), 7.36-7.20 (m, 7H), 4.26 (s, 2H), 3.48 (m, 3H), 3.30-3.00 (m,2H), 3.07 (s, 3H). 2-[4′-(2-Benzyl- Isolated as a white foam. R_(f) 0.41(20% benzofuran-3-yl)- Methanol-80% Ethyl Acetate); ¹H NMR (CDCl₃)biphenyl-4- 7.74-7.56 (m, 9H), 7.42 (d, J = 7.8 Hz, sulfonylamino]-3-(4-1H), 7.29-7.14 (m, 7H), 7.05 (dd, J₁ = 8.6 fluoro-phenyl)-propionic Hz,J₂ = 5.6 Hz, 2H), 6.84 (t, J = 8.6 Hz, acid; 2H), 4.28 (s, 2H),4.10-4.03 (s, 1H), 3.08 (dd, J₁ = 5.0 Hz, J₂ = 13.5 Hz, 1H), 2.91 (dd,J₁ = 14.0 Hz, J₂ = 6.8 Hz, 1H). 2-{[4′-(2-Benzyl- Isolated as anoff-white solid. R_(f) 0.52 benzofuran-3-yl)- (20% Methanol-80%Methylene Chloride); ¹H biphenyl-4-sulfonyl]- NMR (DMSO-d₆) 8.35 (br s,1H), 7.82-6.90 methyl-amino}-3-(4- (m, 20H), 4.26 (s, 2H), 3.93 (m, 1H),2.97 fluoro-phenyl)-propionic (m, 1H), 2.72 (m, 1H), 2.47 (s, 3H). acid;2-[4′-(2-Benzyl- Isolated as a white solid. R_(f) 0.42benzofuran-3-yl)-biphenyl-4- (20% Methanol-80% Ethyl Acetate); ¹H NMRsulfonylamino]-3-(3- (DMSO-d₆) 8.66 (d, J = 9.3 Hz, 1H), 7.94fluoro-phenyl)-propionic (d, J = 8.0 Hz, 2H), 7.90 (d, J = 8.4 Hz, acid;2H), 7.80-7.66 (m, 6H), 7.46-7.28 (m, 8H), 7.07 (d, J = 8.4 Hz, 2H),4.38 (s, 2H), 4.14 (m, 1H), 3.08 (J₁ = 13.7 Hz, J₂ = 5.3 Hz, 1H),2.93-2.85 (m, 1H). 2-{[4′-(2-Benzyl- Isolated as an off-white solid.R_(f) 0.20 benzofuran-3-yl)- (10% Methanol-90% Methylene Chloride); ¹Hbiphenyl-4-sulfonyl]- NMR (DMSO-d₆) 7.88 (d, J = 8.4 Hz, 2H),methyl-amino}-3-(3- 7.80 (d, J = 8.4 Hz, 2H), 7.71-7.53 (m, 6H),fluoro-phenyl)-propionic 7.36-7.20 (8H), 7.09-6.98 (m, 3H), 4.83 acid;(dd, J₁ = 10.8 Hz, J₂ = 4.8 Hz, 1H), 4.29 (s, 2H), 3.19 (dd, J₁ = 14.1Hz, J₂ = 5.1 Hz, 1H), 2.95 (dd, J₁ = 14.7 Hz, J₂ = 10.8 Hz, 1H), 2.82(s, 3H). 2-{[4′-(2-Benzyl- Isolated as a white solid. R_(f) 0.38 (10%benzofuran-3-yl)- Methanol-90% Methylene Chloride); ¹H NMRbiphenyl-4-sulfonyl]- (DMSO-d₆) 7.94-7.54 (m, 10H), 7.38-7.00ethyl-amino}-3-(4-fluoro- (m, 11H), 4.69 (s, 2H), 3.33 (m,phenyl)-propionic acid; integration for 2H obscured by H₂O), 2.93 (m,1H), 1.07 (t, J = 9 Hz, 3H). 2-[4′-(2-Benzyl- Isolated as an off-whitefoam. R_(f) 0.24 benzofuran-3-yl)- (10% Methanol-90% MethyleneChloride); ¹H biphenyl-4- NMR (DMSO-d₆) 12.61 (br s, 1H), 8.22 (d,sulfonylamino]-4-methyl- J = 8.4 Hz, 1H), 7.92-7.56 (10H), 7.34-7.25pentanoic acid; (m, 7H), 4.28 (s, 2H), 3.68 (m, 1H), 1.59- 1.24 (m, 3H),0.82 (d, J = 6.3 Hz, 3H), 0.70 (d, J = 6.6 Hz, 3H). 2-[4′-(2-Benzyl-Isolated as a beige foam. R_(f) 0.43 (20% benzofuran-3-yl)- Methanol-80%Methylene Chloride); ¹H NMR biphenyl-4- (DMSO-d₆) 7.92-7.56 (m, 10H),7.31-7.23 sulfonylamino]-propionic (m, 7H), 4.28 (s, 2H), 3.65 (m, 1H),1.20 acid; (d, J = 6.6 Hz, 3H). 2-[4′-(2-Benzyl- Isolated as a whitesolid. R_(f) 0.20 (10% benzofuran-3-yl)- Methanol-90% MethyleneChloride); ¹H NMR biphenyl-4- (DMSO-d₆) 12.6 (br s, 1H), 8.18 (d, J =8.4 sulfonylamino]-butyric Hz, 1H), 7.95-7.84 (m, 7H), 7.70-7.56 (m,acid; 3H), 7.34-7.23 (m, 7H), 4.29 (s, 2H), 3.66 (m, 1H), 1.57 (m, 2H),0.79 (d, J = 7.2 Hz, 3H). 2-(4′-Dibenzofuran-4- Isolated as an off-whitesolid. R_(f) 0.20 yl-biphenyl-4- (10% Methanol-90% Methylene Chloride);¹H sulfonylamino)-3-phenyl- NMR (DMSO-d₆) 8.06 (t, J = 7.5 HZ, 2H), 7.95propionic acid; (d, J = 8.1 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.69-7.28(m, 9H), 7.05-7.04 (m, 5H), 3.83 (m, 1H), 2.87 (dd, J₁ = 5.4 Hz, J₂ =13.8 Hz, 1H), 2.64 (dd, J₁ = 9.6 Hz, J₂ = 13.8 Hz, 1H); LCMS m/z calcdfor C₃₃H₂₅NO₅S: 547.62 found 548.3 (M + 1). (4′-Dibenzofuran-4- Isolatedas a white solid. R_(f) 0.47 yl-biphenyl-4- (20% Methanol-80% MethyleneChloride); ¹H sulfonylamino)-phenyl- NMR (DMSO-d₆) 12.98 (br s, 1H),8.79 (d, acetic acid; J = 9.0 Hz, 1H), 8.18 (t, J = 7.2 Hz, 2H), 8.04(d, J = 8.4 Hz, 2H), 7.90-7.73 (m, 8H), 7.54-7.42 (m, 3H), 7.28-7.21 (m,5H), 4.95 (d, J = 9.3 Hz, 1H). 1-{4-[4-(4-Chloro- R_(f) 0.08 (20%methanol in phenyl)-5-(4-ethyl- dichloromethane ) phenyl)-thiazol-2-ylcarbamoyl]- benzenesulfonyl}- pyrrolidine-2-carboxylic acid;and pharmaceutically acceptable salts thereof.

EXAMPLE 4 Method for Measuring PTP-1B Activity

The test compounds are evaluated for their in vitro inhibitory activityagainst recombinant human PTP1B with phosphotyrosyl dodecapeptideTRDI(P)YETD(P)Y(P) YRK [SEQ ID NO:1]. This corresponds to the 1142-1153insulin receptor kinase regulatory domain, phosphorylated on the 1146,1150 and 1151 tyrosine residues; IR-triphosphopeptide as a source ofsubstrate. Enzyme reaction progression is monitored via the release ofinorganic phosphate as detected by the malachite green—ammoniummolybdate method for the phosphopeptide.

Preferred compounds of the invention exhibit IC₅₀ values of less than 10μM; more preferred compounds of the invention exhibit IC₅₀ values ofless than 1 μM. Particularly preferred compounds exhibit IC₅₀ values ofless than 300 nM.

The invention and the manner and process of making and using it, are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the invention and that modifications may be made thereinwithout departing from the spirit or scope of the invention as set forthin the claims. To particularly point out and distinctly claim thesubject matter regarded as invention, the following claims conclude thisspecification.

1. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, 3,or 4; R₁ is H, C₁-C₆ alkyl, phenyl(C₁-C₆)alkyl, or C₃-C₆ alkenyl; R₂ isphenyl, phenyl(C₁-C₄) alkyl, C₁-C₆ alkyl, —(C₁-C₄) alkyl-C(O)NH₂,—(C₁-C₄) alkyl-C(O)NH(C₁-C₄)alkyl, —(C₁-C₄) alkyl-C(O)N(C₁-C₄)alkyl(C₁-C₄) alkyl, —(C₁-C₄) alkyl-S(O)_(b)—(C₁-C₄) alkyl, (C₁-C₄)hydroxyalkyl, —(C₁-C₄) alkyl-heterocycloalkyl, wherein theheterocycloalkyl group is optionally fused to a phenyl ring and whereinthe heterocycloalkyl portion, the phenyl portion, or both are optionallysubstituted with a total of 1, 2, 3, or 4 groups that are independentlyhalogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, —SO₂—(C₁-C₄) alkyl, haloalkyl, orhaloalkoxy; wherein b is 0, 1, or 2; R₂₀, R₂₁, R₂₂, and R₂₃ areindependently H, arylalkoxy, arylalkyl, halogen, alkyl, haloalkyl, OH,alkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆ alkyl) (C₁-C₆ alkyl), NH-aryl,NHC(O)—(C₁-C₄ alkyl)-aryl, N(C₁-C₄ alkyl)C(O)—(C₁-C₄)alkyl-aryl,N(C₁-C₄)alkyl-aryl, —NHSO₂-aryl, or —N(C₁-C₄alkyl)SO₂aryl, wherein eachof the above aryl groups are optionally substituted with 1, 2, 3, or 4groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, OH,NO₂, haloalkyl, haloalkoxy; L is —SO₂NH—, —SO₂N(C₁-C₄) alkyl-, —NHSO₂—,—N(C₁-C₄alkyl)SO₂—, O, —C(O)NH—, —C(O)N(C₁-C₄)alkyl-, —SO₂—,—C(O)—(C₁-C₄) alkyl-, —(C₁-C₄) alkyl-C(O)—, —NH—, —(C₁-C₆ alkyl)-O—N═,or —N(C₃-C₄ alkyl)-, wherein the alkyl group is optionally substitutedwith phenyl, wherein the phenyl is optionally substituted with 1, 2, 3,or 4 groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen,OH, NO₂, haloalkyl, or haloalkoxy; L₃ is a bond, absent,—(C₁-C₄)alkyl-O—, —O—(C₁-C₄)alkyl, —(C₁-C₄) alkyl-, —C(O)—, —C(O)NH—, or—NHC(O)—; the A-ring is aryl selected from the group consisting ofphenyl, naphthyl and fluorenyl, or heteroaryl, each of which isoptionally substituted with 1, 2, or 3 groups that are independently,halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy,NO₂, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆) alkyl (C₁-C₆) alkyl; Q is H, aryl,heteroaryl, -heteroaryl-alkyl, -aryl-heteroaryl, aryl-C(O)-aryl,aryl-(C₁-C₄ alkyl)-aryl, heteroaryl-(C₁-C₄ alkyl)-aryl,-heteroaryl-aryl, wherein the aryl group is a phenyl, naphthyl, orfluorenyl, each of which is optionally substituted with 1, 2, 3, or 4groups that are independently C₁-C₆ alkyl, C₁-C₄ alkoxycarbonyl, C₁-C₆alkoxy, halogen, haloalkyl, haloalkoxy, NR₆R₇, or phenyl; wherein R₆ andR₇ are independently H, C₁-C₆ alkyl, aryl(C₁-C₆)alkyl, alkanoyl,arylalkanoyl, alkoxycarbonyl, arylalkoxycarbonyl, heteroarylcarbonyl,heteroaryl, heterocycloalkylcarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl,—C(O)N(C₁-C₆) alkyl(C₁-C₆)alkyl, or —SO₂-aryl, wherein the cyclic groupsare optionally substituted with 1, 2, 3, or 4 groups that areindependently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, NO₂, OH, NH₂,NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, haloalkyl or haloalkoxy.
 2. Acompound according to claim 1, wherein R₂ is phenyl, phenyl(C₁-C₄)alkyl, C₁-C₆ alkyl, —(C₁-C₄) alkyl-C(O)NH₂, —(C₁-C₄)alkyl-C(O)NH(C₁-C₄)alkyl, —(C₁-C₄) alkyl-C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl,—(C₁-C₄) alkyl-S(O)_(b)—(C₁-C₄) alkyl, (C₁-C₄) hydroxyalkyl, —(C₁-C₄)alkyl-phthalimidyl, —(C₁-C₄) alkyl-piperidinyl, —(C₁-C₄)alkyl-pyrrolidinyl, —(C₁-C₄) alkyl-morpholinyl, wherein thephthalimidyl, piperidinyl, pyrrolidinyl, or morpholinyl groups areoptionally fused to a phenyl ring and wherein said phthalimidyl,piperidinyl, pyrrolidinyl, or morpholinyl groups are, the phenylportion, or both are optionally substituted with a total of 1, 2, 3, or4 groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy,—SO₂—(C₁-C₄) alkyl (C₁-C₄)haloalkyl, or (C₁-C₄)haloalkoxy; wherein b is0, 1, or 2; and Q is H, pyrido[1,2-a]indolyl, indolyl, isoindolyl,indolizinyl, imidazo[1,2-a]pyridine, -phenyl-C(O)-phenyl,-phenyl-(C₁-C₄) alkyl-phenyl, -pyridyl-phenyl, fluorenyl,-fluorenyl-pyridyl, -fluorenyl-phenyl, -benzofuranyl-(C₁-C₄)alkyl-phenyl, -benzimidazolyl-(C₁-C₄) alkyl-phenyl, benzoxazolyl-(C₁-C₄)alkyl-phenyl, indolizinyl, benzofuranyl, -indolyl-(C₁-C₄) alkyl-phenyl,-phenyl-benzoxazolyl, benzo[b]thienyl, dibenzo[b,d]furan, phenyl, ordibenzothienyl, each of which is optionally substituted with 1, 2, 3, or4 groups that are independently C₁-C₆ alkyl, C₁-C₄ alkoxycarbonyl, C₁-C₆alkoxy, halogen, haloalkyl, haloalkoxy, NR₆R₇, or phenyl; wherein R₆ andR₇ are independently H, C₁-C₆ alkyl, aryl(C₁-C₆)alkyl, alkanoyl,phenyl(C₁-C₄)alkanoyl, alkoxycarbonyl, phenyl(C₁-C₄) alkoxycarbonyl,pyridylcarbonyl, pyridyl, piperidinyl, pyrrolidinylcarbonyl, —C(O)NH₂,—C(O)NH(C₁-C₆)alkyl, —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, or —SO₂-phenyl,wherein the cyclic groups are optionally substituted with 1, 2, 3, or 4groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, NO₂,OH, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, CF₃ or OCF₃.
 3. Acompound according to claim 2, wherein the A-ring is selected fromphenyl, naphthyl, pyridyl, thiazolyl, benzofuranyl, dibenzofuranyl,pyrrolyl, furanyl, isoindolyl, or indolyl each of which is optionallysubstituted with 1, 2, or 3 groups that are independently, halogen,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, NO₂, NH₂,NH(C₁-C₆)alkyl, or N(C₁-C₆)alkyl(C₁-C₆) alkyl; and R₂₀, R₂₁, R₂₂, andR₂₃ are independently H, phenylalkoxy, phenylalkyl, halogen, alkyl, CF₃,OH, alkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl,NH-phenyl, NHC(O)—(C₁-C₄) alkyl-phenyl, N(C₁-C₄ alkyl)C(O)—(C₁-C₄)alkyl-phenyl, N(C₁-C₄)alkyl-phenyl, —NHSO₂-phenyl, or—N(C₁-C₄alkyl)SO₂-phenyl, wherein the phenyl groups are optionallysubstituted with 1, 2, 3, or 4 groups that are independently C₁-C₆alkyl, C₁-C₆ alkoxy, halogen, OH, NO₂, C₁-C₂ haloalkyl, or C₁-C₂haloalkoxy.
 4. A compound according to claim 3, wherein L is —SO₂NH—,—SO₂N(C₁-C₄) alkyl-, —NHSO₂, O, —C(O)NH—, —C(O)N(C₁-C₄)alkyl-, —SO₂—,—C(O)—(C₁-C₄) alkyl-, —(C₁-C₄) alkyl-C(O)—, —NH—, —N(C₁-C₄) alkyl-,wherein the alkyl group is optionally substituted with phenyl, which isoptionally substituted with 1, 2, 3, or 4 groups that are independentlyC₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, OH, NO₂, C₁-C₄ haloalkyl, or C₁-C₄haloalkoxy.
 5. A compound according to claim 4, of the formula

wherein R₁ is H or C₁-C₆ alkyl; R₂ is phenyl, phenyl(C₁-C₄) alkyl, C₁-C₆alkyl, —(C₁-C₄) alkyl-C(O)NH₂, —(C₁-C₄) alkyl-S(O)_(b)—(C₁-C₄) alkyl, or(C₁-C₄) hydroxyalkyl, wherein the phenyl groups are optionallysubstituted with 1, 2, 3, or 4 groups that are independently halogen,C₁-C₄ alkyl, C₁-C₄ alkoxy, —SO₂—(C₁-C₄) alkyl, (C₁-C₄)haloalkyl, or(C₁-C₄)haloalkoxy; v is 0, 1, 2, 3, or 4; R₁₀ at each occurrence isindependently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄haloalkoxy, NO₂, NH₂, NH(C₁-C₆)alkyl, or N(C₁-C₆)alkyl(C₁-C₆)alkyl; andL₃ is a bond, absent, —O—(C₁-C₄)alkyl, —(C₁-C₄) alkyl-, or —C(O)—.
 6. Acompound according to claim 5, wherein Q is H, pyrido[1,2-a]indolyl,indolyl, imidazo[1,2-a]pyridine, -phenyl-C(O)-phenyl, -phenyl-(C₁-C₄)alkyl-phenyl, fluorenyl, -benzofuranyl-(C₁-C₄) alkyl-phenyl,indolizinyl, benzofuranyl, -indolyl-(C₁-C₄) alkyl-phenyl,-phenyl-benzoxazolyl, benzo[b]thienyl, dibenzo[b,d]furan, phenyl, ordibenzothienyl, each of which is optionally substituted with 1, 2, 3, or4 groups that are independently C₁-C₆ alkyl, C₁-C₄ alkoxycarbonyl, C₁-C₆alkoxy, halogen, haloalkyl, haloalkoxy, NR₆R₇, or phenyl; wherein R₆ andR₇ are independently H, C₁-C₆ alkyl, aryl(C₁-C₆)alkyl, alkanoyl,phenyl(C₁-C₄) alkanoyl, alkoxycarbonyl, phenyl(C₁-C₄) alkoxycarbonyl,pyridylcarbonyl, pyridyl, pyrrolidinylcarbonyl, or —SO₂-phenyl, whereinthe cyclic groups are optionally substituted with 1, 2, 3, or 4 groupsthat are independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, NO₂, OH, NH₂,NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, CF₃ or OCF₃.
 7. A compoundaccording to claim 6, wherein R₂ is phenyl, phenyl(C₁-C₄) alkyl, or(C₁-C₆)alkyl, wherein the phenyl groups are optionally substituted with1, 2, 3, or 4 groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, or —SO₂—(C₁-C₄) alkyl, CF₃ or OCF₃; and R₂₀, R₂₁, R₂₂, and R₂₃are independently selected from H, halogen, alkyl, OH, alkoxy, NO₂, NH₂,NH(C₁-C₆)alkyl, or N(C₁-C₆alkyl) (C₁-C₆alkyl).
 8. A compound accordingto claim 7, wherein L₃ is a bond, —O—(C₁-C₄)alkyl, —(C₁-C₄) alkyl-, or—C(O)—; Q is indolyl, -phenyl-C(O)-phenyl, -benzofuranyl-(C₁-C₄)alkyl-phenyl, indolizinyl, benzofuranyl, -indolyl-(C₁-C₄)alkyl-phenyl,benzo[b]thienyl, dibenzo[b,d]furan, phenyl, or dibenzothienyl, each ofwhich is optionally substituted with 1, 2, 3, or 4 groups that areindependently C₁-C₆ alkyl, C₁-C₄ alkoxycarbonyl, C₁-C₆ alkoxy, halogen,haloalkyl, haloalkoxy, NR₆R₇, or phenyl; wherein R₆ and R₇ areindependently H, C₁-C₆ alkyl, phenyl(C₁-C₆)alkyl, alkanoyl,phenyl(C₁-C₄)alkanoyl, alkoxycarbonyl, pyridylcarbonyl, pyridyl,pyrrolidinylcarbonyl, or —SO₂-phenyl, wherein the cyclic groups areoptionally substituted with 1, 2, 3, or 4 groups that are independentlyhalogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, NO₂, OH, NH₂, NH(C₁-C₆)alkyl,N(C₁-C₆)alkyl(C₁-C₆)alkyl, CF₃ or OCF₃.
 9. A compound according to claim8 of the formula:


10. A compound according to claim 9, wherein L is —SO₂NH—, —SO₂N(C₁-C₄alkyl)-, or —SO₂— wherein the alkyl group is optionally substituted withphenyl, which is optionally substituted with 1, 2, 3, or 4 groups thatare independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, OH, NO₂, C₁-C₄haloalkyl, or C₁-C₄ haloalkoxy.
 11. A compound according to claim 10,wherein R₁ is H; R₂₁ is H, NO₂, C₁-C₆ alkyl, or halogen; and R₂ isphenyl, benzyl, or (C₁-C₆)alkyl, wherein each phenyl group is optionallysubstituted with 1, 2, 3, or 4 groups that are independently halogen,C₁-C₄ alkyl, C₁-C₄ alkoxy, or —SO₂—(C₁-C₄) alkyl, CF₃ or OCF₃.
 12. Acompound according to claim 11, wherein L₃ is a bond, —O—(C₁-C₄)alkyl,or —(C₁-C₄) alkyl-; Q is -benzofuranyl-(C₁-C₄) alkyl-phenyl,indolizinyl, benzofuranyl, dibenzo[b,d]furan, or dibenzothienyl, each ofwhich is optionally substituted with 1, 2, 3, or 4 groups that areindependently C₁-C₆ alkyl, C₁-C₄ alkoxycarbonyl, C₁-C₆ alkoxy, halogen,haloalkyl, haloalkoxy, NR₆R₇, or phenyl; wherein R₆ and R₇ areindependently H, C₁-C₆ alkyl, phenyl(C₁-C₆)alkyl, alkanoyl,phenyl(C₁-C₄)alkanoyl, alkoxycarbonyl, pyridylcarbonyl, pyridyl,pyrrolidinylcarbonyl, or —SO₂-phenyl, wherein the cyclic groups areoptionally substituted with 1, 2, 3, or 4 groups that are independentlyhalogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, NO₂, OH, NH₂, NH(C₁-C₆)alkyl,N(C₁-C₆)alkyl(C₁-C₆)alkyl, CF₃ or OCF₃.
 13. A compound according toclaim 9, wherein L is —O—.
 14. A compound according to claim 13, whereinR₁ is H; R₂₁ is H, NO₂, C₁-C₆ alkyl, or halogen; and R₂ is phenyl,phenyl(C₁-C₄)alkyl, or (C₁-C₆)alkyl, wherein each phenyl group isoptionally substituted with 1, 2, 3, or 4 groups that are independentlyhalogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, or —SO₂—(C₁-C₄) alkyl, CF₃ or OCF₃.15. A compound according to claim 14, wherein L₃ is a bond,—O—(C₁-C₄)alkyl, or —(C₁-C₄) alkyl-; Q is indolyl, -phenyl-C(O)-phenyl,-benzofuranyl-(C₁-C₄) alkyl-phenyl, indolizinyl, benzofuranyl, or-indolyl-(C₁-C₄) alkyl-phenyl, each of which is optionally substitutedwith 1, 2, 3, or 4 groups that are independently C₁-C₆ alkyl, C₁-C₄alkoxycarbonyl, C₁-C₆ alkoxy, halogen, haloalkyl, haloalkoxy, NR₆R₇, orphenyl; wherein R₆ and R₇ are independently H, C₁-C₆ alkyl,phenyl(C₁-C₆)alkyl, alkanoyl, phenyl(C₁-C₄)alkanoyl, alkoxycarbonyl,pyridylcarbonyl, pyrrolidinylcarbonyl, or —SO₂-phenyl, wherein thecyclic groups are optionally substituted with 1, 2, 3, or 4 groups thatare independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, NO₂, OH, NH₂,NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, CF₃ or OCF₃.
 16. A compoundaccording to claim 9, wherein L is —C(O)NH—, —C(O)N(C₁-C₄)alkyl-,—C(O)—(C₁-C₄) alkyl-, —NH—, or —N(C₁-C₄) alkyl-, wherein the alkylgroups are optionally substituted with phenyl, which is optionallysubstituted with 1, 2, 3, or 4 groups that are independently C₁-C₆alkyl, C₁-C₆ alkoxy, halogen, OH, NO₂, C₁-C₂ haloalkyl, or C₁-C₂haloalkoxy.
 17. A compound according to claim 14, wherein L is —C(O)NH—,or —C(O)N(C₁-C₄)alkyl-; R₁ is H; R₂₁ is H, NO₂, C₁-C₆ alkyl, or halogen.18. A compound according to claim 17 R₂ is phenyl, phenyl(C₃-C₄)alkyl,or (C₁-C₆)alkyl, wherein each phenyl group is optionally substitutedwith 1, 2, 3, or 4 groups that are independently halogen, C₁-C₄ alkyl,C₁-C₄ alkoxy, or —SO₂—(C₁-C₄) alkyl, CF₃ or OCF₃.
 19. A compoundaccording to claim 18, wherein L₃ is a bond, —O—(C₁-C₄)alkyl, or—(C₁-C₄) alkyl-; Q is indolyl, -phenyl-C(O)-phenyl,-benzofuranyl-(C₃-C₄) alkyl-phenyl, indolizinyl, benzofuranyl, or-indolyl-(C₁-C₄)alkyl-phenyl, each of which is optionally substitutedwith 1, 2, 3, or 4 groups that are independently C₁-C₆ alkyl, C₁-C₄alkoxycarbonyl, C₁-C₆ alkoxy, halogen, haloalkyl, haloalkoxy, NR₆R₇, orphenyl; wherein R₆ and R₇ are independently H, C₁-C₆ alkyl,phenyl(C₁-C₆)alkyl, alkanoyl, phenyl(C₁-C₄)alkanoyl, alkoxycarbonyl,pyridylcarbonyl, pyrrolidinylcarbonyl, or —SO₂-phenyl, wherein thecyclic groups are optionally substituted with 1, 2, 3, or 4 groups thatare independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, NO₂, OH, NH₂,NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, CF₃ or OCF₃.
 20. A compoundaccording to claim 5, wherein L is —NH—, or —N(C₁-C₄) alkyl-.
 21. Acompound according to claim 20, wherein R₁ is H; R₂₁ is H, NO₂, C₁-C₆alkyl, or halogen; and R₂ is phenyl, phenyl(C₁-C₄) alkyl, C₁-C₆ alkyl,—(C₁-C₄) alkyl-C(O)NH₂, —(C₁-C₄) alkyl-S(O)_(b)—(C₁-C₄) alkyl, or(C₁-C₄) hydroxyalkyl, wherein the phenyl groups are optionallysubstituted with 1, 2, 3, or 4 groups that are independently halogen,C₁-C₄ alkyl, C₁-C₄ alkoxy, —SO₂—(C₁-C₄) alkyl, CF₃ or OCF₃.
 22. Acompound according to claim 21, wherein L₃ is a bond, —O—(C₁-C₄)alkyl,or —(C₁-C₄) alkyl-; Q is indolyl, -phenyl-C(O)-phenyl,-benzofuranyl-(C₁-C₄) alkyl-phenyl, indolizinyl, benzofuranyl, or-indolyl-(C₁-C₄)alkyl-phenyl, each of which is optionally substitutedwith 1, 2, 3, or 4 groups that are independently C₁-C₆ alkyl, C₁-C₄alkoxycarbonyl, C₁-C₆ alkoxy, halogen, haloalkyl, haloalkoxy, NR₆R₇, orphenyl; wherein R₆ and R₇ are independently H, C₁-C₆ alkyl,phenyl(C₁-C₆)alkyl, alkanoyl, phenyl(C₁-C₄)alkanoyl, alkoxycarbonyl,pyridylcarbonyl, pyrrolidinylcarbonyl, or —SO₂-phenyl, wherein thecyclic groups are optionally substituted with 1, 2, 3, or 4 groups thatare independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, NO₂, OH, NH₂,NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆)alkyl, CF₃ or OCF₃.
 23. A compoundaccording to claim 2, of the formula:

wherein v is 0, 1, 2, 3, or 4; R₁₀ at each occurrence is independentlyhalogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy,NO₂, NH₂, NH(C₁-C₆)alkyl, or N(C₁-C₆)alkyl(C₁-C₆)alkyl; and L is—C(O)—(C₁-C₄) alkyl-, —(C₁-C₄) alkyl-C(O)—, wherein the alkyl groups areoptionally substituted with phenyl, which is optionally substituted with1, 2, 3, or 4 groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy,halogen, OH, NO₂, C₁-C₄ haloalkyl, or C₁-C₄ haloalkoxy.
 24. A compoundaccording to claim 23, wherein R₁ is H; R₂₀, R₂₂, and R₂₃ areindependently selected from H, halogen, alkyl, OH, alkoxy, NO₂, NH₂,NH(C₁-C₆)alkyl, or N(C₁-C₆alkyl) (C₁-C₆alkyl); R₂₁ is H, NO₂, C₁-C₆alkyl, or halogen; and R₂ is phenyl, phenyl(C₁-C₄) alkyl, C₁-C₆ alkyl,—(C₁-C₄) alkyl-phthalimidyl, —(C₁-C₄) alkyl-piperidinyl, —(C₁-C₄)alkyl-pyrrolidinyl, —(C₁-C₄) alkyl-morpholinyl, wherein thephthalimidyl, piperidinyl, pyrrolidinyl, or morpholinyl groups areoptionally fused to a phenyl ring and wherein said phthalimidyl,piperidinyl, pyrrolidinyl, or morpholinyl groups are, the phenylportion, or both are optionally substituted with a total of 1, 2, 3, or4 groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy,—SO₂—(C₁-C₄) alkyl (C₁-C₄)haloalkyl, or (C₁-C₄)haloalkoxy; wherein b is0, 1, or
 2. 25. A compound according to claim 21, wherein L₃ is a bond,—O—(C₁-C₄)alkyl, or —(C₁-C₄) alkyl-; Q is indolyl, -phenyl-C(O)-phenyl,-benzofuranyl-(C₁-C₄) alkyl-phenyl, indolizinyl, benzofuranyl,-indolyl-(C₁-C₄)alkyl-phenyl, dibenzo[b,d]furan, or dibenzothienyl, eachof which is optionally substituted with 1, 2, 3, or 4 groups that areindependently C₁-C₆ alkyl, C₁-C₄ alkoxycarbonyl, C₁-C₆ alkoxy, halogen,haloalkyl, haloalkoxy, NR₆R₇, or phenyl; wherein R₆ and R₇ areindependently H, C₁-C₆ alkyl, phenyl(C₁-C₆)alkyl, alkanoyl,phenyl(C₁-C₄)alkanoyl, alkoxycarbonyl, pyridylcarbonyl,pyrrolidinylcarbonyl, or —SO₂-phenyl, wherein the cyclic groups areoptionally substituted with 1, 2, 3, or 4 groups that are independentlyhalogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, NO₂, OH, NH₂, NH(C₁-C₆)alkyl,N(C₁-C₆)alkyl(C₁-C₆)alkyl, CF₃ or OCF₃.
 26. A compound according toclaim 25, wherein R₂ is —(C₁-C₄) alkyl-phthalimidyl, —(C₁-C₄)alkyl-piperidinyl, —(C₁-C₄) alkyl-pyrrolidinyl, —(C₁-C₄)alkyl-morpholinyl, wherein the phthalimidyl, piperidinyl, pyrrolidinyl,or morpholinyl groups are optionally fused to a phenyl ring and whereinsaid phthalimidyl, piperidinyl, pyrrolidinyl, or morpholinyl groups are,the phenyl portion, or both are optionally substituted with a total of1, 2, 3, or 4 groups that are independently halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, —SO₂—(C₁-C₄) alkyl (C₁-C₄)haloalkyl, or (C₁-C₄)haloalkoxy.
 27. Acompound according to claim 26, wherein L₃ is a bond, —O—(C₁-C₄)alkyl,or —(C₁-C₄) alkyl-; Q is indolyl, -benzofuranyl-(C₁-C₄) alkyl-phenyl,indolizinyl, benzofuranyl, -indolyl-(C₁-C₄) alkyl-phenyl, ordibenzo[b,d]furan, each of which is optionally substituted with 1, 2, 3,or 4 groups that are independently C₁-C₆ alkyl, C₁-C₄ alkoxycarbonyl,C₁-C₆ alkoxy, halogen, CF₃ or OCF₃.
 28. A pharmaceutical compositioncomprising a compound according to claim 1 and at least onepharmaceutically acceptable solvent, carrier, excipient or adjuvant. 29.A method of treating diabetes in a patient needing such treatmentcomprising administering a compound of claim 1 or a pharmaceuticalcomposition of claim
 28. 30. A compound according to claim 1 selectedfrom the group consisting of({4′-[3-(benzylamino)imidazo[1,2-a]pyridin-2-yl]biphenyl-4-yl}oxy)(phenyl)aceticacid; {[4′-(5-methyl-1H-indol-1-yl)biphenyl-4-yl]oxy}(phenyl)aceticacid;({4′-[3-(butylamino)imidazo[1,2-a]pyridin-2-yl]biphenyl-4-yl}oxy)(phenyl)aceticacid; methyl({4′-[(2-benzoylphenoxy)methyl]biphenyl-4-yl}oxy)(phenyl)acetate; methyl({4′-[(2-benzylphenoxy)methyl]biphenyl-4-yl}oxy)(phenyl)acetate; methyl({4′-[(9H-fluoren-2-yloxy)methyl]biphenyl-4-yl}oxy)(phenyl)acetate;methyl ({4′-[(3-benzoylphenoxy)methyl]biphenyl-4-yl}oxy)(phenyl)acetate;({4′-[(3-benzoylphenoxy)methyl]biphenyl-4-yl}oxy)(phenyl)acetic acid;({4′-[(2-benzoylphenoxy)methyl]biphenyl-4-yl}oxy)(phenyl)acetic acid;2-([4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]oxy)-3-phenylpropanoicacid; {[4′-(1-butylindolizin-2-yl)biphenyl-4-yl]oxy}(phenyl)acetic acid;[4-(1-benzyl-1H-indol-6-yl)phenoxy](phenyl)acetic acid;({4′-[10-(ethoxycarbonyl)pyrido[1,2-a]indol-3-yl]biphenyl-4-yl}oxy)(phenyl)aceticacid; {[4′-(1-benzofuran-2-yl)biphenyl-4-yl]oxy}(phenyl)acetic acid;{[4′-(1H-indol-1-yl)biphenyl-4-yl]oxy}(phenyl)acetic acid; methyl{[4′-(1-benzyl-1H-indol-6-yl)biphenyl-4-yl]oxy}(phenyl)acetate;4-(4′-Dibenzofuran-4-yl-biphenyl-4-yl)-4-oxo-2-(3-trifluoromethyl-benzyl)-butyricacid {[4′-(1-benzyl-1H-indol-6-yl)biphenyl-4-yl]oxy}(phenyl)acetic acid;{[4′-(1-benzyl-1H-indol-5-yl)biphenyl-4-yl]oxy}(phenyl)acetic acid;2-{[4′-(1-butylindolizin-2-yl)biphenyl-4-yl]oxy}propanoic acid;N-{[4′-(1-butylindolizin-2-yl)biphenyl-4-yl]sulfonyl}phenylalanine;N-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]sulfonyl}phenylalanine;N-benzyl-N-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]sulfonyl}glycine;({[4-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]sulfonyl}amino)(phenyl)aceticacid;(2R)-2-{[4′-(1-butylindolizin-2-yl)biphenyl-4-yl]oxy}-3-phenylpropanoicacid;(2S)-2-{[4′-(1-butylindolizin-2-yl)biphenyl-4-yl]oxy}-4-phenylbutanoicacid;({4′-[(2-butyl-1-benzofuran-3-yl)methyl]biphenyl-4-yl}oxy)(phenyl)aceticacid; ethylN-{([4-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]sulfonyl}-N-methylphenylalaninate;N-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]sulfonyl}-N-methylphenylalanine;ethylN-{[4′-(1-butylindolizin-2-yl)biphenyl-4-yl]carbonyl}phenylalaninate;N-{[4′-(1-butylindolizin-2-yl)biphenyl-4-yl]carbonyl}phenylalanine;{([2′-(1,3-benzoxazol-2-yl)-1,1′:4′,1″-terphenyl-4-yl]oxy}(phenyl)aceticacid;({4′-[(2-butyl-1-benzofuran-3-yl)carbonyl]biphenyl-4-yl}oxy)(phenyl)aceticacid; methyl{[4′-(1-butylindolizin-2-yl)biphenyl-4-yl]sulfonyl}(phenyl)acetate;N-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]carbonyl}phenylalanine;N-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]carbonyl}-N-methylphenylalanine;{[4′-(1-butylindolizin-2-yl)biphenyl-4-yl]sulfonyl}(phenyl)acetic acid;({[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]carbonyl}amino)(phenyl)aceticacid; 2-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]oxy}propanoicacid; {[4′-(1-butylindolizin-2-yl)biphenyl-4-yl]amino}(phenyl)aceticacid;N-({4′-[(2-butyl-1-benzofuran-3-yl)methyl]biphenyl-4-yl}sulfonyl)-N-methylphenylalanine;N-({4′-[(2-butyl-1-benzofuran-3-yl)methyl]biphenyl-4-yl}carbonyl)-N-methylphenylalanine;N-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]carbonyl}-N-methylvaline;2-benzyl-4-[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]-4-oxobutanoicacid;N-[4′-(2-benzyl-1-benzofuran-3-yl)-3-nitrobiphenyl-4-yl]phenylalanine;N-[4′-(2-benzyl-1-benzofuran-3-yl)-3-nitrobiphenyl-4-yl]-N-methyl-L-phenylalanine;N-[4′-(2-benzyl-1-benzofuran-3-yl)-3-nitrobiphenyl-4-yl]-N-methyl-D-phenylalanine;N-{[4′-(2-benzyl-1-benzofuran-3-yl)-3-fluorobiphenyl-4-yl]sulfonyl}phenylalanine;{[4′-(1-benzothien-2-yl)biphenyl-4-yl]oxy}(phenyl)acetic acid;N-[4′-(2-benzyl-1-benzofuran-3-yl)-3-nitrobiphenyl-4-yl]-N-(4-nitrobenzoyl)-L-phenylalanine;[(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)oxy](phenyl)acetic acid;N-{[4′-(2-benzyl-1-benzofuran-3-yl)-3-fluorobiphenyl-4-yl]sulfonyl}-N-methylphenylalanine;[(4″-butyl-1,1′:4′,1″-terphenyl-4-yl)oxy](phenyl)acetic acid;N²-[4′-(2-benzyl-1-benzofuran-3-yl)-3-nitrobiphenyl-4-yl]glutamine;4-[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-4-oxobutanoicacid;({4′-[(2-benzyl-7-fluoro-1-benzofuran-3-yl)carbonyl]biphenyl-4-yl}oxy)(phenyl)aceticacid;N-[4′-(2-benzyl-1-benzofuran-3-yl)-3-nitrobiphenyl-4-yl]methionine;N-[4′-(2-benzyl-1-benzofuran-3-yl)-3-nitrobiphenyl-4-yl]serine;N-[4′-(2-benzyl-1-benzofuran-3-yl)-3-nitrobiphenyl-4-yl]alanine;N-{4′-[(2-benzyl-7-ethoxy-1-benzofuran-4-yl)methyl]-3-nitrobiphenyl-4-yl}phenylalanine;N-[4′-(2-benzyl-4-fluoro-1-benzofuran-3-yl)-3-nitrobiphenyl-4-yl]phenylalanine;2-benzyl-4-[4′-(2-benzyl-1-benzofuran-3-yl)-3,5-dimethylbiphenyl-4-yl]-4-oxobutanoicacid;2-benzyl-4-[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-3-yl]-4-oxobutanoicacid;2-benzyl-4-[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-2-yl]-4-oxobutanoicacid;N-{4′-(2-benzyl-1-benzofuran-3-yl)-3-[(phenylacetyl)amino]biphenyl-4-yl}phenylalanine;4-[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]-2-[4-(methylsulfonyl)benzyl]-4-oxobutanoicacid;N-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]sulfonyl}-4-fluorophenylalanine;N-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]sulfonyl}-4-fluoro-N-methylphenylalanine;N-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]sulfonyl}-3-fluorophenylalanine;N-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]sulfonyl}-3-fluoro-N-methylphenylalanine;N-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]sulfonyl}-N-ethyl-4-fluorophenylalanine;N-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]sulfonyl}leucine;N-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]sulfonyl}alanine;2-({[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]sulfonyl}amino)butanoicacid;4-(4-Dibenzofuran-4-yl-phenyl)-4-oxo-2-(3-trifluoromethyl-benzyl)-butyricacid;N-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]sulfonyl}-N-[3-(trifluoromethyl)benzyl]leucine;2-{{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]sulfonyl}[3-(trifluoromethyl)benzyl]amino}butanoicacid; methyl4-(4′-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)-4-oxo-2-[3-(trifluoromethyl)benzyl]butanoate;[(4′-{[(9-oxo-9H-fluoren-1-yl)oxy]methyl}biphenyl-4-yl)oxy](phenyl)aceticacid; methyl {[4′-(1-benzofuran-2-yl)biphenyl-4-yl]oxy}(phenyl)acetate;({4′-[3-(butylamino)imidazo[1,2-a]pyridin-2-yl]biphenyl-4-yl}amino)(phenyl)aceticacid; {[4′-(1-benzothien-3-yl)biphenyl-4-yl]oxy}(phenyl)acetic acid;methyl {[4′-(1-benzyl-1H-indol-5-yl)biphenyl-4-yl]oxy}(phenyl)acetate;ethyl({[4-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]sulfonyl}amino)(phenyl)acetate;methyl 2-(4-benzo[b]naphtho[2,3-d]furan-11-ylphenoxy)propanoate;3-({[4-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]carbonyl}amino)butanoicacid;N-{[4-(5-methyl-1H-indol-1-yl)biphenyl-4-yl]carbonyl}phenylalanine;N-{[4-(1H-indol-1-yl)biphenyl-4-yl]carbonyl}-L-phenylalanine;N-(3-fluoro-3-nitro-1,1′:4′,1″-terphenyl-4-yl)phenylalanine;2-benzyl-4-[4-(1H-indol-1-yl)biphenyl-4-yl]-4-oxobutanoic acid;2-[4-(2-Benzyl-benzofuran-3-yl)-3-nitro-biphenyl-4-ylamino]-3-phenyl-propionicacid;4-(4-dibenzo[b,d]furan-4-ylbiphenyl-4-yl)-4-oxo-2-[3-(trifluoromethyl)benzyl]butanoicacid; [(4-dibenzo[b,d]thien-4-ylbiphenyl-4-yl)oxy](phenyl)acetic acid;2-[4-(2-Benzyl-benzofuran-3-yl)-3-fluoro-biphenyl-4-sulfonylamino]-3-phenyl-propionicacid;2-{[4-(2-Benzyl-benzofuran-3-yl)-3-fluoro-biphenyl-4-sulfonyl]-methyl-amino}-3-phenyl-propionicacid;4-[4-(2-Benzyl-benzofuran-3-yl)-biphenyl-4-yl]-2-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-4-oxo-butyricacid;2-Benzyl-4-[4-(2-benzyl-benzofuran-3-yl)-3,5-dimethyl-biphenyl-4-yl]-4-oxo-butyricacid; 2-Benzyl-4-(4-indol-1-yl-biphenyl-4-yl)-4-oxo-butyric acid;2-Benzyl-4-[4-(2-benzyl-benzofuran-3-yl)-biphenyl-3-yl]-4-oxo-butyricacid;2-Benzyl-4-[4-(2-benzyl-benzofuran-3-yl)-biphenyl-2-yl]-4-oxo-butyricacid;4-[4-(2-Benzyl-benzofuran-3-yl)-biphenyl-4-yl]-2-(4-methanesulfonyl-benzyl)-4-oxo-butyricacid;2-[4-(2-Benzyl-benzofuran-3-yl)-biphenyl-4-sulfonylamino]-3-(4-fluoro-phenyl)-propionicacid;2-{[4-(2-Benzyl-benzofuran-3-yl)-biphenyl-4-sulfonyl]-methyl-amino}-3-(4-fluoro-phenyl)-propionicacid;2-[4-(2-Benzyl-benzofuran-3-yl)-biphenyl-4-sulfonylamino]-3-(3-fluoro-phenyl)-propionicacid;2-{[4-(2-Benzyl-benzofuran-3-yl)-biphenyl-4-sulfonyl]-methyl-amino}-3-(3-fluoro-phenyl)-propionicacid;2-{[4-(2-Benzyl-benzofuran-3-yl)-biphenyl-4-sulfonyl]-ethyl-amino}-3-(4-fluoro-phenyl)-propionicacid;2-[4′-(2-Benzyl-benzofuran-3-yl)-biphenyl-4-sulfonylamino]-4-methyl-pentanoicacid;2-[4′-(2-Benzyl-benzofuran-3-yl)-biphenyl-4-sulfonylamino]-propionicacid; 2-[4′-(2-Benzyl-benzofuran-3-yl)-biphenyl-4-sulfonylamino]-butyricacid;2-(4′-Dibenzofuran-4-yl-biphenyl-4-sulfonylamino)-3-phenyl-propionicacid; (4′-Dibenzofuran-4-yl-biphenyl-4-sulfonylamino)-phenyl-aceticacid;2-{[4-(2-Dibenzofuran-4-yl-thiazol-4-yl)-benzenesulfonyl]-ethyl-amino}-3-phenyl-propionicacid; (4′-Dibenzofuran-4-yl-biphenyl-4-ylmethoxyimino)-phenyl-aceticacid;3-(4′-Dibenzofuran-4-yl-biphenyl-4-ylmethoxyimino)-3-phenyl-propionicacid; [4′-(5-Chloro-indol-1-yl)-biphenyl-4-yloxy]-phenyl-acetic acid;(3-Chloro-4′-dibenzofuran-4-yl-biphenyl-4-yloxy)-phenyl-acetic acid;(4′-Dibenzofuran-4-yl-2-methyl-biphenyl-4-yloxy)-phenyl-acetic acid;(4′-Dibenzofuran-4-yl-3-fluoro-biphenyl-4-yloxy)-phenyl-acetic acid;(2-Chloro-4′-dibenzofuran-4-yl-biphenyl-4-yloxy)-phenyl-acetic acid; and(4′-Dibenzofuran-4-yl-2-trifluoromethyl-biphenyl-4-yloxy)-phenyl-aceticacid.